ANRV371-IY27-09 ARI 16 February 2009 8:57

ANNUAL
REVIEWS Further The Inflammasomes:
Guardians of the Body
Click here for quick links to
Annual Reviews content online,
including:
• Other articles in this volume
• Top cited articles
• Top downloaded articles Fabio Martinon,1 Annick Mayor,2 and Jürg Tschopp2
Annu. Rev. Immunol. 2009.27:229-265. Downloaded from arjournals.annualreviews.org

• Our comprehensive search

by Universidad Nacional Autonoma de Mexico on 03/24/09. For personal use only.

1
Department of Immunology and Infectious Diseases, Harvard School of Public Health,
Boston, Massachusetts 02115
2
Department of Biochemistry, University of Lausanne, 1066 Epalinges, Switzerland;
email: jurg.tschopp@unil.ch

Annu. Rev. Immunol. 2009. 27:229–65 Key Words

First published online as a Review in Advance on
December 8, 2008
The Annual Review of Immunology is online at
immunol.annualreviews.org
This article’s doi:
10.1146/annurev.immunol.021908.132715
Copyright  c 2009 by Annual Reviews.
All rights reserved
0732-0582/09/0423-0229$20.00
adjuvanticity, danger signal, inflammation, innate immunity,
NOD-like receptors
Abstract
The innate immune system relies on its capacity to rapidly detect in-
vading pathogenic microbes as foreign and to eliminate them. The
discovery of Toll-like receptors (TLRs) provided a class of membrane
receptors that sense extracellular microbes and trigger antipathogen
signaling cascades. More recently, intracellular microbial sensors have
been identified, including NOD-like receptors (NLRs). Some of the
NLRs also sense nonmicrobial danger signals and form large cytoplas-
mic complexes called inflammasomes that link the sensing of microbial
products and metabolic stress to the proteolytic activation of the proin-
flammatory cytokines IL-1β and IL-18. The NALP3 inflammasome
has been associated with several autoinflammatory conditions includ-
ing gout. Likewise, the NALP3 inflammasome is a crucial element in the
adjuvant effect of aluminum and can direct a humoral adaptive immune
response. In this review, we discuss the role of NLRs, and in partic-
ular the inflammasomes, in the recognition of microbial and danger
components and the role they play in health and disease.

229
 ANRV371-IY27-09 ARI 16 February 2009 8:57
INTRODUCTION
AND OVERVIEW
Vertebrates have evolved two complementary
Pattern-recognition
receptor (PRR): systems to detect and clear pathogens: the in-
membrane receptor nate and the adaptive immune systems. The
expressed by cells of innate immune system is the first one to be
the immune system to
activated by pathogens (1) and is usually suffi-
identify molecules
cient to clear the infection. However, when the
associated with
microbial pathogens or innate immune system is overwhelmed, it trig-
cellular stress gers and directs the adaptive arm, thus activat-
Pathogen-associated ing specific B and T cells for pathogen clear-
molecular pattern ance. Receptors expressed by B and T cells are
(PAMP): highly generated through somatic gene rearrangement
Annu. Rev. Immunol. 2009.27:229-265. Downloaded from arjournals.annualreviews.org
conserved microbial
by Universidad Nacional Autonoma de Mexico on 03/24/09. For personal use only.
and hypermutation. This process enables the
structure that is
generation of a virtually infinite repertoire of
essential for microbial
survival and is detected antigen receptors, allowing the adaptive im-
by host innate immune munity to specifically recognize any type of
receptors microorganism.
Danger signal: signal In contrast, innate immunity is character-
released by injured or ized by its ability to recognize a wide range of
damaged tissues that
pathogens such as viruses, bacteria, and fungi,
trigger an innate
but through a limited number of germline-
immune response
encoded receptors called pattern-recognition
Toll-like receptor
receptors (PRRs) (2, 3). PRRs are expressed by
(TLR): membrane
receptor involved in many cell types including macrophages, mono-
innate immune sensing cytes, dendritic cells (DCs), neutrophils, and
epithelial cells, and they allow the early de-
tection of pathogens directly at the site of in-
fection. PRRs recognize conserved microbial
signatures (4) termed pathogen-associated
molecular patterns, or PAMPs (see below).
Once activated, the innate immune system ini-
tiates the inflammatory response by secreting
cytokines and chemokines, inducing the expres-
sion of adhesion and costimulatory molecules
in order to recruit immune cells to the site of
infection and to trigger the adaptive immune
response.
Pathogens can rapidly evolve and, in prin-
ciple, could avoid detection by the innate im-
mune system by simply altering the targeted
PAMPs. By doing so, the pathogen would not
only escape the recognition by the innate im-
mune system but also avoid the adaptive im-
mune response. However, the immune system
has evolved to recognize PAMPs that are es-
sential for the viability of microbes and are
thus less prone to modifications. PAMPs can
230 Martinon · Mayor · Tschopp
be of diverse origins; sugars, flagellin, and the
cell wall components peptidoglycan (PGN) and
lipopolysaccharide (LPS) are all recognized by
the innate immune system.
The model proposed by Charles Janeway
based on PAMP recognition is, however, too
simplistic. Indeed, if PAMPs activate the im-
mune pathway, how does the immune system
distinguish pathogenic microorganisms from
commensal and other non-pathogenic bacteria?
To answer this question, Matzinger (5, 6) sug-
gested that the activation of the innate immune
system is not only based on the recognition of
PAMPs but also relies on the presence of danger
signals or danger-associated molecular patterns
(DAMPs) released by injured cells. These two
models seem completely opposed, but several
reports now show activation of innate immu-
nity by host molecules. Indeed among others,
mammalian dsDNA (7) and uric acid crystals
(8) activate an inflammatory response.
The release of DAMPs is a common event,
as tissue damage and cell lysis are often associ-
ated with infections and lead to the release of
host molecules. Recognition of these DAMPs
by the immune system not only allows the sens-
ing of an ongoing infection and subsequent re-
cruitment of more immune cells, but also can
initiate the repair of the damaged tissue (9). It
seems then that the innate immune pathway not
only scans the cellular environment for signs
of invading pathogens, but also recognizes the
damage caused by them.
PAMPs are recognized by PRRs that are
either cytoplasmic, membrane-bound, or se-
creted; the most intensely studied are the
Toll-like receptors (TLRs). These receptors
are expressed by many cell types including
mononuclear, endothelial, and epithelial cells.
Once activated by PAMPs, the TLRs induce
different signaling cascades depending on the
adaptor protein, ultimately leading to the ac-
tivation of the transcription factors NF-κB,
AP-1, and interferon-regulatory factor (IRF)-
3. TLR activation results in the production
of antimicrobial peptides, inflammatory cy-
tokines and chemokines, tumor necrosis factor
(TNF)-α, and costimulatory and adhesion
 ANRV371-IY27-09 ARI 16 February 2009 8:57
molecules, as well as in the upregulation of ma-
jor histocompatibility complexes (MHCs). As
one given pathogen does not trigger only one
specific TLR, but rather a set of TLRs leading
to the expression of different proteins depend-
ing on the nature of the activated TLRs, the
immune system is instructed on the type of the
invading microorganism and mounts the most
appropriate response to fight it. Excellent re-
views on the biology of TLRs have been pub-
lished recently (10–12). TLRs are therefore not
the focus of this review.
Recently, two other families of PRRs were
Annu. Rev. Immunol. 2009.27:229-265. Downloaded from arjournals.annualreviews.org
by Universidad Nacional Autonoma de Mexico on 03/24/09. For personal use only.
described: the NLRs (NOD-like receptors) and
the RLHs (RIG-like helicases). Unlike TLRs,
these families consist of soluble proteins that
survey the cytoplasm for signs that advertise the
presence of intracellular invaders. Two RNA
helicases, namely RIG-I and MDA5 (13–15),
were identified as cytoplasmic, viral RNA sen-
sors. Upon viral stimulation of the two RLHs,
NF-κB and IRF3/7 are activated and, in turn,
induce the transcription of type I interferon
(IFN). Based on the CARD (caspase recruit-
ment domain) homology with RIG-I or MDA5,
the CARD adaptor (Cardif, also known as IPS-
1, MAVS, or VISA) that induces IFN-β was
identified (16–18). Both the CARD domain and
the mitochondrial localization of Cardif are re-
quired to induce NF-κB and IRF3/7 activation
(16, 18).
Studies on TLR signaling pathways and
the analysis of key TLR-deficient mice re-
vealed that TLRs could not be the only in-
nate immune receptors responsible for cytokine
production. Indeed, computational analysis of
the genome identified the NLR proteins.
NLR proteins are intracellular LRR (leucine-
rich repeat)-containing proteins that resemble
plant disease–resistance genes. The character-
ization of these NLRs has advanced greatly
in recent years, underscoring their essential
roles in innate immunity. In particular, cy-
toplasmic complexes called inflammasomes,
in which the scaffolding and sensing pro-
teins are members of the NLR family, have
been found to be central platforms of innate
immunity.
In this review, we examine the remarkably
important and emerging functions of inflam-
masomes as guardians of the body. We begin
NOD-like receptor
by describing the general molecular nature of (NLR): cytosolic
the inflammasome complexes and the known protein involved in
pathways that activate them. We then highlight innate immune sensing
the current understanding of the function of RIG-like helicase
this pathway—its role in orchestrating host de- (RLH): cytosolic
fenses and in the pathogenesis of inflammatory helicase involved in
innate immune sensing
diseases.
of nucleic acids
Inflammasome:
THE NLR FAMILY molecular complex
involved in the
In recent years, the central role of the NLR activation of
family has become increasingly appreciated (19, inflammatory caspases
20). NLRs form central molecular platforms resulting in the
processing of
that organize signaling complexes such as in-
immature proIL-1β
flammasomes and NOD signalosomes. Most and proIL-18 into
NLRs are expressed in the cytosol. Structurally, their mature forms
NLRs are multidomain proteins with a tripar- NOD signalosome:
tite architecture containing a C-terminal region complex that is
characterized by a series of LRRs, a central assembled upon
nucleotide domain termed the NACHT do- oligomerization of
NOD1 or NOD2 that
main (also referred to as NOD domain), and an
activates RIP2 and
N-terminal effector domain (Figure 1). triggers NF-κB
The LRR domain has been implicated in activation
ligand sensing and autoregulation of NLRs,
yet the precise mechanism of how NLR LRRs
sense their ligands is largely unknown. The
LRR is a widespread structural motif of 20–30
amino acids with a characteristic pattern rich
in the hydrophobic amino acid leucine. LRR
domains are formed by tandem repeats of a
structural unit consisting of a β strand and an
α helix, and are organized in such a way that
all the β strands and the helices are parallel
to the same axis, resulting in a nonglobular,
horseshoe-shaped molecule with the curved β
parallel sheet lining the inner circumference
and the α helices lining the outer circumfer-
ence (21). These modules are associated with
a wide range of functions including a role as
pathogen sensors in various innate immune re-
ceptors such as TLRs and NLRs. TLRs con-
tain LRRs that recognize or sense the pres-
ence of a wide range of PAMPs including LPS,
lipoproteins, flagellin, and RNA from bacteria
or viruses. They are believed to sense directly
www.annualreviews.org • The Inflammasomes 231
 ANRV371-IY27-09 ARI 16 February 2009 8:57

NOD-like receptors

NALP1
CARD
NOD1
NALP3 NOD3 NLRX1/
FIIND NAIP CIITA Plant
NALP4-14 NOD4 NOD2 NOD5 APAF1
NLR
IPAF

LRR WD40

NAD
NB-
ARC
NACHT
Annu. Rev. Immunol. 2009.27:229-265. Downloaded from arjournals.annualreviews.org

AD
BIR TIR
by Universidad Nacional Autonoma de Mexico on 03/24/09. For personal use only.

PYD CARD

NALPs IPAF/NAIP NODs

Figure 1
Domain organization of representative NOD-like receptors (NLRs). NLRs are characterized by three distinct domains: the
ligand-sensing leucine-rich repeats (LRRs); the NACHT domain, which is responsible for the capacity of NLRs to oligomerize; and
the effector domain, which can be a pyrin domain (PYD), CARD, or BIR domain. Most NLRs also contain a NACHT-associated
domain (NAD) C-terminal of the NACHT domain. NLRs are divided into two large subfamilies: the 14 members of the
PYD-containing NALP clan and the five members of the NODs and CIITA. IPAF and the BIR-containing NAIP form the remaining
NLR members. For comparison, the structural organization of a plant NLR-like gene and APAF1 are shown. (Abbreviations: CARD,
caspase recruitment domain; PYD, pyrin domain; FIIND, function to find; NACHT, domain conserved in NAIP, CIITA, HET-E and
TP1; NAD, NACHT-associated domain; BIR, baculovirus IAP repeat; AD, activation domain; NALP, NACHT, LRR, and
PYD-containing protein; CIITA, MHC class II transcription activator; IPAF, ICE-protease-activating factor.)

or indirectly their activating PAMPs. Double- domains belong to the recently defined
Apoptosome:
oligomeric structure stranded RNA and lipopeptides have recently STAND family of NTPases (24). Oligomeriza-
that is assembled when been shown to bind TLR3 and TLR1/TLR2 tion has been reported for several STAND fam-
APAF1 interacts with complexes, respectively, whereas LPS-induced ily proteins, as well as in other related AAA+
cytochrome c released TLR4 activation is presumed to be indirect and NTPases. Similarly, it is believed that the
from mitochondria;
to involve binding of LPS to MD2 (22, 23). In crucial step in NLR activation lies in the
triggers apoptosis by
activating caspase-9 contrast, no experimental data have convinc- oligomerization of the NACHT domain,
ingly demonstrated a direct interaction between thereby forming active, high molecular weight
STAND family of
NTPases: Subfamily the LRRs of NLRs and their respective activa- complexes that characterize inflammasomes
of AAA+ NTPases tors, suggesting that sensing of pathogens and and NOD signalosomes (25, 26).
that includes NLRs other signals by NLRs may be indirect. NLR subfamilies differ in their N-terminal
AAA+ NTPases: The NACHT domain, which is central to effector domains, which mediate signal trans-
superfamily of all NLRs, has similarity to the NB-ARC mo- duction to downstream targets, leading to ac-
ATPases associated tif of the apoptotic mediator APAF1. APAF1 tivation of inflammatory caspases by inflam-
with a variety of
performs its cellular function through the for- masomes or NF-κB by NOD signalosomes.
cellular activities and
characterized by their mation of a caspase-9 activating, heptameric The vast majority of NLRs harbor a death-fold
extended P-loop platform termed an apoptosome. The NB- domain at the N terminus, which is either a
ATPase domain ARC domain is responsible for dATP/ CARD or a pyrin domain (PYD) (Figure 1,
capable of forming ATP-dependent oligomerization of APAF1 Table 1). The death-fold domain superfamily
donut-shaped
upon cytochrome c binding, a process that initi- was originally described in proapoptotic signal-
oligomers
ates apoptosis. Both the NACHT and NB-ARC ing pathways and, in addition to CARD and

232 Martinon · Mayor · Tschopp

 ANRV371-IY27-09 ARI 16 February 2009 8:57

Table 1 NOD-like receptors (NLRs)

NLR Commonly used nomenclature
subfamilya human mouse Other names and aliases Structure
NALPs NALP1 DEFCAP, NAC, CARD7, PYD-NACHT-NAD-LRR-
NLRP1 FIIND-CARD
NALP1a NACHT-NAD-LRR-FIIND-
CARD
NALP1a NACHT-NAD-LRR-FIIND-
CARD
NALP1a NACHT-NAD-LRR-FIIND-
CARD
NALP2 Pypaf2, NBS1, PAN1, NLRP2 PYD-NACHT-NAD-LRR
Annu. Rev. Immunol. 2009.27:229-265. Downloaded from arjournals.annualreviews.org

NALP2 PYD-NACHT-NAD-LRR
by Universidad Nacional Autonoma de Mexico on 03/24/09. For personal use only.

NALP3 Pypaf1, CIAS1, NLRP3 PYD-NACHT-NAD-LRR

(Cryopyrin)
NALP3 Cias1, Pypaf1, Mmig1 PYD-NACHT-NAD-LRR
NALP4 Pypaf4, PAN2, RNH2, NLRP4 PYD-NACHT-NAD-LRR
NALP4a Nalp-η, NALP9D PYD-NACHT-NAD-LRR
NALP4b Nalp-γ, NALP9E PYD-NACHT-NAD-LRR
NALP4c Nalp-α, Rnh2 PYD-NACHT-NAD-LRR
NALP4d Nalp-β PYD-NACHT-NAD-LRR
NALP4e Nalp-ε PYD-NACHT-NAD-LRR
NALP4f Nalp-κ, NALP9F PYD-NACHT-NAD-LRR
NALP4g PYD-NACHT-NAD-LRR
NALP5 Pypaf8, Mater, PAN11, NLRP5 PYD-NACHT-NAD-LRR
NALP5 mater, Op1 NACHT-NAD-LRR
NALP6 Pypaf5, PAN3, NLRP6 PYD-NACHT-NAD-LRR
NALP6 PYD-NACHT-NAD-LRR
NALP7 Pypaf3, NOD12, NLRP7 PYD-NACHT-NAD-LRR
NALP8 PAN4, NOD16, NLRP8 PYD-NACHT-NAD-LRR
NALP9 NOD6, NLRP9 PYD-NACHT-NAD-LRR
NALP9a Nalp-θ PYD-NACHT-NAD-LRR
NALP9b Nalp-δ PYD-NACHT-NAD-LRR
NALP9c Nalp-ζ PYD-NACHT-NAD-LRR
NALP10 PAN5, NOD8, Pynod, NLRP10 PYD-NACHT-NAD
NALP10 Pynod PYD-NACHT-NAD
NALP11 Pypaf6, NOD17, NLRP11 PYD-NACHT-NAD-LRR
NALP12 Pypaf7, Monarch1, RNO2, PYD-NACHT-NAD-LRR
PAN6, NLRP12
NALP12 PYD-NACHT-NAD-LRR
NALP13 NOD14, NLRP13 PYD-NACHT-NAD-LRR
NALP14 NOD5, NLRP14 PYD-NACHT-NAD-LRR
NALP14 Nalp-ι, GC-LRR, PYD-NACHT-NAD-LRR
(Continued )

www.annualreviews.org • The Inflammasomes 233

 ANRV371-IY27-09 ARI 16 February 2009 8:57

Table 1 (Continued )
NLR Commonly used nomenclature
subfamilya human mouse Other names and aliases Structure
IPAF/NAIP Ipaf Ipaf CARD12, CLAN, NLRC4 CARD-NACHT-LRR
Ipaf CARD12, CLAN CARD-NACHT-LRR
NAIP BIRC1 BIR3x-NACHT-LRR
NAIPa Birc1a, NAIP1 BIR3x-NACHT-LRR
NAIPb Birc1b, Naip-rs6, NAIP2 BIR3x-NACHT-LRR
NAIPc Birc1c, Naip-rs5, NAIP3 BIR3x-NACHT-LRR
NAIPd Birc1d, Naip-rs2, NAIP4 BIR3x-NACHT-LRR
NAIPe Birc1e, Naip-rs3, NAIP5 BIR3x-NACHT-LRR
NAIPf Birc1f, Naip-rs4, NAIP6 BIR3x-NACHT-LRR
Annu. Rev. Immunol. 2009.27:229-265. Downloaded from arjournals.annualreviews.org

NAIPg Birc1g, NAIP7 BIR3x-NACHT-LRR

by Universidad Nacional Autonoma de Mexico on 03/24/09. For personal use only.

NODs NOD1 CARD4, CLR7.1 CARD-NACHT-NAD-LRR

NOD1 CARD4 CARD-NACHT-NAD-LRR
NOD2 CARD15, CD, BLAU, IBD1, CARD2x-NACHT-NAD-LRR
PSORAS1, CLR16.3
NOD2 CARD15 CARD2x-NACHT-NAD-LRR
NOD3 CLR16.2, NLRC3 CARD-NACHT-NAD-LRR
NOD3 CARD-NACHT-NAD-LRR
NOD4 NOD27, CLR19.3, NLRC5 CARD-NACHT-LRR
NOD4 CARD-NACHT-LRR
NOD5 (NLRX1) NOD9, CLR11.3, NLRX1 X-NACHT-LRR
NOD5(NLRX1) BC034204 X-NACHT-LRR
CIITA MHC2TA, C2TA (CARD)-AD-NACHT-NAD-LRR
CIITA C2TA (CARD)-AD-NACHT-NAD-LRR

a
NLRs are divided into two large subfamilies: the 14 members of the PYD-containing NALP clan and the five members of the NODs and CIITA. IPAF
and the BIR-containing NAIP form the remaining NLR members.

PYD, includes the death domain (DD) and the
death effector domain (DED) (27). The death-
fold domain is characterized by six α helices
that are tightly packed in a Greek key fold and
form trimers or dimers with other members
of the same subfamily. In most known cases
a DD interacts with a DD, a CARD with a
CARD, a DED with a DED, and a PYD with a
PYD. These four domains are frequently found
in pathways that lead to the activation of cas-
pases or that activate the transcription factor
NF-κB. The observation that every death-fold-
containing family member is able to interact
with another partner harboring the same do-
main was instrumental in the identification of
major signaling pathways involved in apoptosis
and immunity. The death fold acts as a molec-
ular velcro that bridges receptors to adaptors
and effector proteins. Similarly, the N-terminal
PYD or CARD present in NLRs recruits PYD-
or CARD-containing molecules to signaling
platforms.
NLR Subfamilies
Structurally and functionally, NLRs are di-
vided into subfamilies. In this review, we use
the nomenclature that is most commonly used
and highlight the various NLR subfamilies. An
overview of the family members and their his-
torical or alternative nomenclature is listed in
Table 1. The NLR family emerged almost
ten years ago with the cloning of NOD1 and
NOD2 and the subsequent identification of

234 Martinon · Mayor · Tschopp

 ANRV371-IY27-09 ARI 16 February 2009 8:57

the PYD domain (28–31). Based on phyloge-
netic distribution, we distinguish three differ-
ent NLR subfamilies, all characterized by a spe-
cific molecular structure (29, 32) (Figure 1).
NALPs represent the largest NLR subfamily
and have 14 genes identified in humans (29)
(Table 1). Some of them, such as NALP1,
NALP2, and NALP3, were shown to be the
central scaffold of caspase-1-activating com-
plexes known as inflammasomes. NALP pro-
teins harbor a NACHT and a LRR and are
characterized by an N-terminal PYD domain.
Interestingly, the LRR region within NALPs
Annu. Rev. Immunol. 2009.27:229-265. Downloaded from arjournals.annualreviews.org
by Universidad Nacional Autonoma de Mexico on 03/24/09. For personal use only.
transcriptional regulation of genes encoding
MHC II (34). NOD5/NLRX1 is recruited to
the outer membrane of mitochondria (35). The
function of NOD5/NLRX1 is still controver-
sial. One study suggested that NOD5/NLRX1
interacts and negatively regulates the antivi-
ral pathway involving the CARD-containing
adapter MAVS/CARDIF/IPS-1/VISA (36),
whereas another study proposed that NLRX1
promotes the production of reactive oxygen
species (ROS) (37). NOD3 and NOD4 have
no identified functions yet.

is organized in the genome in a very con- NLR Expression Patterns

served and precise manner. NALP LRR re- and Gene Regulation
gions are formed by tandem repeats of ex-
Expression patterns of most NLRs in vari-
ons of exactly 171 nucleotides and are defined
ous cell populations and tissues have not yet
completely by a preserved intron-exon struc-
been studied in detail. Nevertheless, the im-
ture. Each exon encodes one central LRR and
portance of NLRs in defense strategies of the
two halves of the neighboring LRRs (33). The
body is supported by the fact that several NLRs
phasing and position of the introns are consis-
are expressed in cells and tissues that have a
tent with rapid and efficient exon amplification
role in immunity such as phagocytes. Some
during evolution. This particular modular or-
NLRs are also critical in epithelial cells, which
ganization possibly allows extensive alternative
form the first barrier of defense against bac-
splicing of the LRR region without disturbing
teria in human tissues and express NOD1,
the three-dimensional fold of the region and,
NOD2, NALP3, and NAIP (20, 38, 39).
as a consequence, maximizing variability in the
NALP1 is widely expressed, whereas NALP3 is
ligand-sensing unit.
found mainly in immune cells, epithelial cells,
Evolutionarily, IPAF and NAIP group to-
and osteoblasts (40). NAIP and IPAF are ex-
gether and are well separated from other NLRs.
pressed in the brain and in macrophages and
IPAF contains an N-terminal CARD, whereas
macrophage-rich tissues such as spleen, lung,
NAIP has three BIR domains, which are often
and liver (41, 42). The expression of some
found in proteins involved in apoptosis such as
NLRs seems to be highly restricted; for ex-
the IAP family of caspase inhibitors. Both IPAF
ample, NALP5, NALP8, NALP4, NALP7,
and NAIP are involved in the formation of in-
NALP10, and NALP11 are mainly expressed
flammasomes, either alone or in combination
in germ cells and preimplantation embryos
with one another.
(43). Most NLRs may be induced by other
The third class of NLRs includes the
branches of the innate immunity as part of a reg-
remaining CARD-containing NLRs such as
ulatory network. TLR stimulation, for exam-
NOD1, NOD2, NOD4, and CIITA. This
ple, increases the expression of NLRs, such as
clade also contains a slightly separated group
NOD1, NOD2, and NALP3, possibly reflect-
with NOD3 and NOD5/NLRX1 (19, 32).
ing enhancement of NLR responses after TLR
NOD5/NLRX1 does not have a defined N-
stimulation (44).
terminal domain, whereas at least one splice
variant of CIITA has been reported to harbor
a CARD. NOD1 and NOD2 activate the tran- NLRs: Lessons from Evolution
scription factor NF-κB, a major regulator of Ever since the discovery of NLRs in mammals,
inflammatory responses. CIITA regulates the the similarity of these genes with a family of

www.annualreviews.org • The Inflammasomes 235

 ANRV371-IY27-09
Annu. Rev. Immunol. 2009.27:229-265. Downloaded from arjournals.annualreviews.org
by Universidad Nacional Autonoma de Mexico on 03/24/09. For personal use only.
ARI 16 February 2009 8:57
plant genes involved in immune defenses has
cross-fertilized NLR research (28). The plant
genes, known as R-genes (R for resistance), are
crucial for the immune defense of plants against
bacteria, fungi, viruses, and other pathogens.
The largest known class of R-genes structurally
resembles mammalian NLRs. They have a
C-terminal LRR, a central oligomerization
module related to the NB-ARC subtype of
STAND domains, and an N-terminal effector
domain that is generally either a coiled-coil do-
main or a TIR domain (45). The TIR domain
is a well-known recruitment domain involved
in the TLR and IL-1R family of immune me-
diators. There are more than 150 NLR-like
R-genes in Arabidopsis (46). Many of these genes
have been implicated in sensing pathogens. The
vast repertoire of NLRs in plants is believed
to be the result of a complex host-pathogen
race that promoted the evolution of specific
NLR genes that genetically interact with spe-
cific avirulence genes from distinct pathogens
(47). Although plant NLR-like proteins are
functionally and structurally similar to mam-
malian NLRs, there is no evidence for a com-
mon evolutionary origin. It is more likely that
these innate immune sensors are an exam-
ple of convergent evolution. The NLR struc-
ture (based on a C-terminal LRR sensing unit,
a STAND oligomerization module, and an
N-terminal recruitment domain) probably
originated independently through evolution,
which emphasizes key molecular constraints
required to design successful innate immune
systems (48, 49). Supporting the convergent
evolution idea, no NLR-like proteins have been
found in insects. In the animal kingdom, the
first evolutionarily conserved NLRs are ob-
served in the echinoderm sea urchin.
The observation by Mechnikov of phagocy-
tosis in echinoderms is considered to be a crit-
ically defining moment that led to the original
concept of immune defenses and, more specifi-
cally, innate immunity (50). More than one cen-
tury after these experiments, the sequencing of
the sea urchin genome provided us with another
appreciation of the complexity and general con-
servation of innate immune system mechanisms
236 Martinon · Mayor · Tschopp
(51, 52). The sea urchin genome contains 222
TLRs and 203 NLRs. Interestingly, most of the
NLRs are expressed in the gut, suggesting that
gut-related immunity is a likely driving force
behind the expansion of this family in echino-
derms (51). These findings highlight NLRs as
well as TLRs as evolutionarily important im-
mune genes that preceded the acquisition of the
adaptive immune system in vertebrates.
In nonmammalian vertebrates such as ze-
brafish, three distinct families of NLRs have
been identified (53, 54). The first subfam-
ily is related to the NOD subclass of mam-
malian NLRs and contains orthologs of NOD1,
NOD2, NOD3, and NOD4. The second sub-
family resembles the NALPs and contains at
least six genes. Finally, the last subfamily has the
highest similarity with the NACHT domain of
NOD3 and has expanded in teleost fish into sev-
eral hundreds of predicted genes. Most of these
genes encode a PYD domain at the N terminus
(similar to the one that characterizes NALPs).
Interestingly, some of these NLRs have a
C-terminal extension following the LRR that
contains a PRY-SPRY domain. The PRY-SPRY
domain is also found in human Pyrin, a PYD-
containing regulator of the inflammasome (see
below). The precise role of the PRY-SPRY in
Pyrin or in nonmammalian, vertebrate NLRs is
unknown; however, this finding further high-
lights the role of Pyrin and possibly other
PRY-SPRY-containing proteins in the regula-
tion of NLRs (55, 56).
Extensive diversification of the NLRs oc-
curred also within the mammalian lineage; this
is particularly true for NALPs that mainly
evolved through gene duplication events. Some
NALPs such as NALP2 and NALP7 in hu-
mans are clearly paralogs, whereas others, such
as NALP4 and NALP9, expanded only in the
mouse (Table 1). A similar evolutionary trend
was followed by NAIP in mice, where the locus
expanded to seven NAIP genes (33).
All these observations indicate that the NLR
repertoire within a species, and across verte-
brates, is large. Some of these NLRs have un-
dergone lineage-specific amplification, such as
NOD3-related NLRs in zebrafish or NALPs in
 ANRV371-IY27-09 ARI 16 February 2009 8:57
mammals. Genes involved in interactions with
pathogens are likely to diversify by undergoing
lineage-specific expansion (57), reflecting the
adaptive dynamics of a species to new environ-
ments with emerging pathogens.
NOD Signalosomes
NOD1 was one of the first NLRs to be de-
scribed (58, 59). Both NOD1 and NOD2,
once activated, recruit and engage the ki-
nase RIP2 through CARD-CARD interac-
tions. Oligomerization of RIP2 in the NOD
Annu. Rev. Immunol. 2009.27:229-265. Downloaded from arjournals.annualreviews.org
by Universidad Nacional Autonoma de Mexico on 03/24/09. For personal use only.
signalosome results in the activation of the
transcription factor NF-κB (60). Recently, the
CARD-containing protein CARD9 has also
been found to interact with NOD2 and RIP2
and to be involved in the activation of JNK
and p38 by NOD2 (61). Both NOD1 and
NOD2 detect muropeptides released from bac-
terial PGNs. NOD1 and NOD2 sense dis-
tinct PGN structures. Whereas NOD2 detects
muramyl dipeptides (MDP), the largest motif
common to Gram-negative and Gram-positive
bacteria, NOD1 detects meso-diaminopimelic
acid (meso-DAP), which is mainly found in
Gram-negative bacteria (62, 63). Both PGNs
are degradation products of bacterial cell wall
components released by intracellular or phago-
cytosed bacteria. Pathogens that do not reach
the intracellular compartment of the host cell
may use specialized secretion systems to in-
ject the PGN fragment into the host cytosol.
Helicobacter pylori, for example, elicits NOD1
activation by delivering PGN fragments into
the host cell through a mechanism that requires
a functional type IV secretion system (64).
NOD1 and NOD2 are crucial innate im-
mune receptors in epithelial cells, where
they are important to control infection via
the gastro-intestinal route, for example, by
H. pylori and Listeria monocytogenes (64, 65). Im-
portantly, mutations in NOD2 have been asso-
ciated with Crohn’s disease, a form of inflamma-
tory bowel disease. Most NOD2 mutations in
these patients affect the LRR region of NOD2
and are believed to disrupt the protein’s ability
to sense bacteria (66). This probably confers a
loss of tolerance toward commensal bacteria or
allows the proliferation of pathogenic bacteria
in the gut. Gain-of-function mutations in the
NACHT domain of NOD2 have been shown
to be responsible for Blau syndrome, a rare au-
toinflammatory disorder starting in childhood
and characterized by skin rashes, uveitis, and
joint inflammation (67). More recently, NOD2
has been suggested to play a role in the ac-
tivation of some types of inflammasomes (68,
69). These findings are discussed in more detail
below.
INFLAMMASOMES
The term inflammasome was coined to describe
a high molecular weight complex that activates
inflammatory caspases and the cytokine IL-
1β (70). Inflammasome is assembled from the
word inflammation—to reflect the function of
this complex—and the suffix “some” from the
Greek soma meaning body, which is frequently
used in cell biology to define entities or molec-
ular complexes such as proteasome, liposome,
ribosome, etc. Importantly, the term inflamma-
some was also chosen to highlight structural and
functional similarities with another well-known
caspase-activating complex, the apoptosome, a
molecular platform that triggers apoptosis (71).
Inflammasomes Lead to Activation
of Inflammatory Caspases
Caspases are proteases produced in cells as cat-
alytically inactive zymogens and usually un-
dergo proteolytic processing during activation
(72). The subset of caspases that cleave sub-
strates during apoptosis are known as exe-
cutioner caspases. These executioner caspases
(caspase-3, -6, and -7 in mammals) are gener-
ally activated by the initiator caspases such as
caspase-8, caspase-10, caspase-2, or caspase-9.
Initiator caspases harbor an N-terminal death-
fold domain (CARD or DED in mammals) that
is required for the activation of their C-terminal
catalytic region. The mechanism of activation
of initiator caspases depends on the engage-
ment and activation of platforms such as the
www.annualreviews.org • The Inflammasomes 237
 ANRV371-IY27-09 ARI 16 February 2009 8:57
INFLAMMATORY CASPASES
In mammals, the inflammatory caspases include human and
murine caspase-1, human and murine caspase-12, murine
caspase-11, and the two caspase-1-related human caspases,
caspase-4 and caspase-5 (33, 204). Inflammatory caspases in mam-
mals have a CARD domain followed by a domain containing the
catalytic residue cysteine. These caspases are termed inflamma-
tory because the main substrates of caspase-1 identified to date
are cytokines (such as IL-1β, IL-18, and possibly IL-33) that
are crucial mediators of the inflammatory response. Caspase-1
was the first caspase to be discovered in mammals, but only re-
Annu. Rev. Immunol. 2009.27:229-265. Downloaded from arjournals.annualreviews.org
by Universidad Nacional Autonoma de Mexico on 03/24/09. For personal use only.
cently have the pathways (inflammasomes) leading to its activa-
tion been discovered (70). Although both human caspase-5 and
mouse caspase-11 have been associated with caspase-1 activation,
no specific substrates have been described for them. Caspase-5 is
recruited by the C-terminal CARD of NALP1, suggesting that
it may be involved in the activity of inflammasomes harboring
NALP1. Caspase-12 and caspase-4 are activated by endoplas-
mic reticulum (ER) stress, an adaptive response that copes with
protein overload in the ER. However, the function of these in-
flammatory caspases upon ER stress is unclear (75). Moreover,
caspase-12 appears to be an inhibitor of the inflammasome, pos-
sibly by interfering with caspase-1 activation, a process that has
been associated with susceptibility to sepsis (209).
death-inducing signaling complex (DISC) for
caspase-8 and -10, the PIDDosome for caspase-
2, and the apoptosome for caspase-9 (73). These
platforms integrate cellular signals, recruit ini-
tiator caspases via their death-fold domain, and
promote dimerization of the caspases, which
all lead to the formation of an active enzyme
proficient enough to initiate specific signaling
cascades (74). Inflammasomes activate a class
of caspases known as inflammatory caspases
(25, 75) (see sidebar, Inflammatory Caspases).
An increasing number of studies highlight the
importance and complexity of inflammatory
caspase activation.
Prototypical Inflammasomes
Although the biochemistry and diversity of in-
flammasomes are still poorly understood, we
238 Martinon · Mayor · Tschopp
distinguish three prototypes of inflammasomes:
The NALP1 inflammasome, the NALP3 in-
flammasome, and the IPAF inflammasome. For
several NALPs, there is evidence for their roles
as scaffolding proteins of inflammasomes (76).
It is assumed that the PYD of NALPs inter-
acts and recruits the adaptor ASC (apoptosis-
associated speck-like protein containing a
caspase recruitment domain) via PYD-PYD
interaction (Figure 2). ASC contains an N-
terminal PYD and a C-terminal CARD and is
an essential component for inflammasome for-
mation (70, 77). The CARD domain within
ASC binds and recruits caspase-1 to the in-
flammasome. NALP1 has a C-terminal exten-
sion that harbors a CARD, which was shown
to recruit caspase-5 (70) or a second caspase-1
(26). Other NALPs do not have the NALP1
C-terminal extension; instead, CARDINAL
(a protein very similar to the NALP1 C termi-
nus) interacts with other inflammasomes such
as the NALP3 or NALP2 inflammasome (78).
Neither CARDINAL nor NALP1 is highly
conserved in mice. The NALP1 locus in mice
contains three paralogs that have no functional
PYD, whereas CARDINAL is not present in
the mouse genome at all. It is therefore pos-
sible that NALP1 genes fulfill CARDINAL
functions in mice. IPAF has an N-terminal
CARD and directly recruits caspase-1 (41)
(Figure 2).
Basic mechanisms implicated in the activa-
tion of NLRs are also involved in inflamma-
some assembly. IPAF and NALP3 selectively
bind ATP/dATP, and nucleotide binding is nec-
essary for oligomerization of the NACHT do-
main (79, 80). Both IPAF and NALP3 bind
SGT1 and HSP90 (81, 82), two proteins whose
plant orthologs were previously shown to regu-
late and interact with plant NLRs. In mammals,
as in plants, the activity of the HSP90-SGT1
complex is essential for NALP3 activation,
probably for keeping the inflammasome inac-
tive but competent for activation. HSP90 has
been suggested to act upstream of NALP1 in-
flammasome activation by anthrax lethal toxin
(83).
 ANRV371-IY27-09 ARI 16 February 2009 8:57

Although the IPAF, NALP3, and NALP1 NALP3 inflammasome IPAF inflammasome
inflammasomes form prototypical inflamma-
NALP3 NALP3 IPAF IPAF
some complexes, recent genetic evidence
suggests that other NLRs, such as NAIP or
NOD2, may be involved in forming inflam-
masomes or in modulating their activity. Ex-
actly how and at what step these proteins are
connected to the formation of inflammasomes ASC
Caspase-1 Caspase-1
are unknown. It is also unclear whether multi-
CARD
ple NLRs may assemble as heterocomplexes to
form competent inflammasomes (84, 85). Thus, CARD ASC
the complexity and diversity of inflammasomes
may turn out to be considerable (86). Caspase-1 Caspase-1
Annu. Rev. Immunol. 2009.27:229-265. Downloaded from arjournals.annualreviews.org
by Universidad Nacional Autonoma de Mexico on 03/24/09. For personal use only.

INFLAMMASOMES AS SENSORS Inflammasome

OF DANGER
Although inflammasomes are emerging more
and more as key players in inflammatory and
immune responses, a growing number of stud-
ies reveal their function in the sensing of a con-
troversial signal: danger. It is well known that
a major function of the immune system is to
differentiate self from nonself—to respond to
self with tolerance and to mount an immune
response against nonself. Innate immunity, for
example, detects PAMPs from microbes, in-
cluding pathogens. There is also evidence
that innate immunity is able to discriminate
pathogenic microbes from nonpathogenic mi-
crobes or commensals; but this raises the ques-
tion of how the immune system interprets the
microbial environment allowing the discrimi-
nation between nonpathogenic and pathogenic
microbes (6). Matzinger and colleagues (87),
to account for some unsolved questions of the
self-from-nonself model, promoted an alterna-
tive hypothesis (the danger hypothesis), sug-
gesting that it is the presentation of an anti-
gen in the context of a danger signal that
triggers an efficient immune response, not sim-
ply the foreignness of the antigen. This led to
multiple studies identifying molecules and sig-
nals that are released by damaged or stressed tis-
sues and that trigger or modulate the immune
response (88, 89). Both the self-from-nonself
model and the danger model may synergize
to determine the quality and extent of the in-
ProIL-1β
IL-1β
Figure 2
Structural organization of the typical NALP3 and IPAF inflammasomes. The
core structure of the NALP3 inflammasome is formed by NALP3, the adaptor
ASC, and caspase-1. PYD-PYD and CARD-CARD homotypic interactions are
crucial for the recruitment and activation of either the adaptor ASC or the
inflammatory caspases (left panel ). IPAF recruits caspase-1 directly via
CARD-CARD interactions (right panel ). The leucine-rich repeats of NALP3
or IPAF are proposed to sense the activating signals leading to the
oligomerization of the NACHT domain and initiating the formation of the
donut-shaped inflammasome. Based on the structure of the apoptosome, the
caspases and IL-1β processing activity most likely face toward the inside of the
donut (lower panel ).
nate immune response (90). Although the dan-
ger hypothesis was first proposed in mammals,
evidence for such a type of immune response
was first documented in plants. Plant immunity
relies on an effector-triggered immunity that
mainly detects pathogen-driven modifications,
stress, or danger signals in the infected host cell
(91). Similarly, the mammalian NLR NALP3
was found to be involved in sensing danger
signals.

www.annualreviews.org • The Inflammasomes 239

 ANRV371-IY27-09 ARI 16 February 2009 8:57

Cell Disruption Activates the
Inflammasome
Early observations that cell lysis in a hypotonic
buffer can lead to the processing of proIL-1β
provided an important model system that
permitted the identification of caspase-1 as
the protease responsible for the processing
of proIL-1β (92). Using this cell-free system,
investigators noticed that caspase-1 activation
was restricted to a few cell types, such as the
monocytic cell line THP-1. A similar assay
subsequently allowed the first biochemical
Annu. Rev. Immunol. 2009.27:229-265. Downloaded from arjournals.annualreviews.org
ings demonstrating that various danger signals
and stimuli that activate the NALP3 inflam-
masome can trigger potassium efflux, thereby
lowering the cytosolic potassium concentration
of stimulated cells (93, 95) (Figure 3).
Sensing Extracellular ATP
Extracellular ATP serves as a danger signal
that alerts the immune system by binding to
the purinoreceptor P2X7, thereby activating
NALP3 and caspase-1 (8, 96–98). Although

identification and characterization of an in- ATP is emerging as an important modulator

by Universidad Nacional Autonoma de Mexico on 03/24/09. For personal use only.

flammasome complex (70). After disruption of
cellular integrity, the inflammasome is sponta-
neously formed. Assembly can be inhibited by
complementing the cell extracts with potassium
levels that mimic normal levels found in the cy-
tosol of healthy cells (over 70 mM) (70, 93, 94).
The observation that subphysiological amounts
of potassium are required for spontaneous
inflammasome formation suggests that the in-
flammasome may sense drops in potassium lev-
els. This possibility is supported by recent find-
of inflammation (99), the critical role of extra-
cellular ATP as a danger signal is unclear. The
amount of extracellular ATP that is required to
activate macrophages in vitro is relatively high
(2 to 5 mM), and, moreover, in vivo most of the
extracellular ATP may be rapidly hydrolyzed by
ectonucleotidases (100). ATP is released from
cells as a consequence of cell damage and/or cel-
lular stress. In endothelial as well as in epithe-
lial cells, ATP release is triggered by nonlytic,
mechanical stimuli as diverse as compression,

K+ efflux
?
Bacterial toxins Danger signals
A. hydrophila (Aerolysin) ROS MSU
Dinoflagellates (Maitotoxin) CPPD Large
L. monocytogenes (LLO) Alum particles
S. aureus Asbestos
NALP3 ATP
ASC
PAMPs Skin irritants
Caspase-
e- UV
Viral DNA NOD2, NALP1?
MDP NALP3 inflammasome

Figure 3
Multiple NALP3 inflammasome activators trigger cellular signals, such as potassium efflux and reactive
oxygen species, that eventually activate an inflammasome dependent on caspase-1, ASC, and NALP3. Note
that muramyl dipeptide (MDP) activation of caspase-1 may also require the NOD-like receptors NOD2 and
NALP1. (Abbreviations: CPPD, calcium pyrophosphate dihydrate crystals; MSU, monosodium urate
crystals; PAMP, pathogen-associated molecular pattern; UV, ultraviolet light.)

240 Martinon · Mayor · Tschopp

 ANRV371-IY27-09 ARI 16 February 2009 8:57
hydrostatic pressure changes, and hypotonic
shock (101). ATP release can also occur through
secretory organelles that store large amounts
of ATP (102). Adrenal medullary chromaffin
granules, which may be released upon physical
or psychological stress, have concentrations of
ATP around 100 mM, whereas platelet-dense
granules contain concentrations of ATP that
can reach 500 mM (100 times more than the
cytosolic concentration). Similarly, secretion of
insulin-containing granules from pancreatic β
cells releases the ATP pool stored in the gran-
ules (103). ATP can also be released from mi-
Annu. Rev. Immunol. 2009.27:229-265. Downloaded from arjournals.annualreviews.org
by Universidad Nacional Autonoma de Mexico on 03/24/09. For personal use only.
crobial flora and pathogens. Salivary histatins,
for example, trigger ATP efflux from Candida
albicans, increasing extracellular ATP, a mech-
anism that may contribute to the antifungal
properties of these proteins (104). Exposure of
cells to extracellular ATP activates caspase-1
(105). Several studies have demonstrated that
ATP-induced caspase-1 activation and subse-
quent IL-1β maturation requires activation of
the purinoreceptor P2X7 in combination with
another type of channel, the pannexin-1 chan-
nel (106). Interestingly, pannexin-1, besides its
role as a gap junction protein, can act as a spe-
cific ATP release channel (107). This suggests
an amplifying mechanism for P2X7-mediated
inflammasome activation via pannexin-1, which
is indeed observed, at least in vitro (108).
The generation of ASC-deficient mice
demonstrated that ATP-mediated caspase-1 ac-
tivation requires ASC, and it was therefore
probably dependent on the activation of a
NALP protein (77, 109). This hypothesis was
confirmed in studies using NALP3-deficient
mice (8, 96–98), demonstrating that extracel-
lular ATP can act as a danger signal to acti-
vate the NALP3 inflammasome and promote
caspase-1 activation and IL-1β maturation.
Although extracellular ATP has been shown
to be involved in inflammatory conditions,
as in asthmatic airway inflammation (110),
the physiological significance of extracellular
ATP-mediated NALP3 inflammasome ac-
tivation still remains to be demonstrated
in vivo.
Uric Acid: A Danger Signal
Involved in Gout
In addition to ATP, cells release other danger
signals to activate the immune system. In a
seminal paper, the Rock laboratory (111) puri-
fied, from the supernatant of dying cells, a low
molecular fraction that could trigger adjuvan-
ticity in vivo and identified uric acid as the active
compound of that fraction. Uric acid is the end
product of the cellular catabolism of purines
and is present at near saturating amounts in
body fluids and at much higher concentration
in the cytosol of healthy cells. It is believed that
extracellular uric acid coming in contact with
the high levels of free sodium present in the
extracellular environment nucleates and forms
monosodium urate (MSU) crystals. MSU is
considered to be the biologically active struc-
ture that is responsible for the adjuvantic effect
of uric acid. Therefore, formation of this dan-
ger signal is the result of a multistep process that
starts with the release of uric acid. The biologi-
cal activity of MSU, including its adjuvanticity,
depends on the activation of the NALP3
inflammasome and the production of IL-1, but
not on TLRs (8, 112, 113). MSU stimulates
the NALP3 inflammasome to produce active
IL-1β (8), and macrophages from mice defi-
cient in components of the inflammasome, such
as caspase-1, NALP3, and ASC, have a highly
reduced crystal-induced IL-1β activation
capacity.
The in vivo relevance of uric acid signals has
been addressed in a follow-up study by Rock
and colleagues (114), who showed that elimi-
nation of uric acid reduced the generation of
cytotoxic T cells to an antigen in transplanted
syngeneic cells and the proliferation of autore-
active T cells in a transgenic diabetes model.
It has also been suggested that erythrocytes
infected with Plasmodium parasites accumulate
high levels of the uric acid precursor hypox-
anthine, which is released and converted into
uric acid upon rupture of the erythrocytes, a
process that results in inflammation (115). Uric
acid release also occurs in DCs incubated in
the presence of alum (aluminum hydroxide),
www.annualreviews.org • The Inflammasomes 241
 ANRV371-IY27-09 ARI 16 February 2009 8:57

which is the most widely used adjuvant in hu-
man vaccines (116). Interestingly, alum was
recently found to be a direct inflammasome
Adjuvant: substance
that enhances the activator (113, 117–119) (see below).
capacity of an antigen High levels of circulating uric acid (hy-
to stimulate the peruricemia) has been associated with vari-
immune system ous inflammatory diseases, including multiple
sclerosis, hypertension, and cardiovascular dis-
eases (120). Hyperuricemia and MSU forma-
tion are strongly linked to gout. The autoin-
flammatory disease gout is characterized by
arthropathies generated by the inflammatory
reaction to MSU in the joints and periarticu-
Annu. Rev. Immunol. 2009.27:229-265. Downloaded from arjournals.annualreviews.org
by Universidad Nacional Autonoma de Mexico on 03/24/09. For personal use only.
comes lodged in the lungs, continuous irrita-
tion ensues, resulting in chronic inflammation
that favors the development of cancer. This, in
particular with asbestos, is associated with the
development of malignant mesotheliomas.
Similar to what was found for MSU, asbestos
and silica microparticles activate the NALP3
inflammasome (127–129). It is significant to
note that pulmonary inflammation is greatly re-
duced in NALP3-deficient mice after in vivo
inhalation of asbestos or silica (127, 128).
Aluminum Particles: An

lar tissues (121). In a model of MSU crystal- Inflammasome-Dependent Adjuvant

induced peritonitis in mice, impaired inflamma-
Vaccine adjuvants are exogenic preparations
tion is found in inflammasome-deficient mice
that boost the immune response to achieve pro-
or mice deficient in the IL-1 receptor (IL-1R)
tective immunity. Most adjuvants activate in-
(8, 112), suggesting that the inflammatory re-
nate immune receptors such as TLRs (130).
sponse in gout is dependent on the inflamma-
More recently, NLRs and inflammasomes were
some. The importance of IL-1 in the pathology
found to respond to specific adjuvants. Alum has
of gout is supported by promising preliminary
been the most widely used adjuvant in human
clinical trials in patients with acute gout. Pa-
vaccination for more than half a century (131).
tients responded positively to the injection of
Among the early observations on the adjuvantic
the IL-1R antagonist IL-1ra (122, 123). Sim-
effect of alum was that immunization with this
ilarly, patients with pseudogout, an inflamma-
adjuvant led to an increase in antigen-induced
tory disease caused by the deposition of calcium
T cell proliferation, apparently resulting from
pyrophosphate dihydrate crystals (CPPD), an-
the augmented production of IL-1 (132). Anti-
other type of pathogenic microcrystal that acti-
IL-1 antibodies are able to inhibit an antigen-
vates the NALP3 inflammasome (8), responded
specific T cell proliferative response after im-
well to treatment with the IL-1ra (124).
munization with alum adjuvant, but not with
Freund’s complete adjuvant (133). The abil-
Silica and Asbestos and Inflammation ity of alum to activate caspase-1 and produce
in the Lung active IL-1β and IL-18 was demonstrated in
vitro (134). Alum-induced caspase-1 activation
Alveolar macrophages reside in the respiratory
depends on the NALP3 inflammasome (113,
surfaces, one of the major boundaries between
117–119). Mice deficient in NALP3, ASC, or
the body and the outside world. These cells are
caspase-1 fail to mount a significant antibody
phagocytes that play an important role in host
response to antigen immunization with alum
defenses against microorganisms and remove
adjuvants (113, 117, 119), confirming that the
particles such as dust. Silica and asbestos dust
NALP3 inflammasome is a key player that links
are particularly strong inflammation inducers
the innate immune system with the adaptive
in the lungs (125). Macrophages can dissolve
immune system.
MSU, but are not able to efficiently eliminate
microparticles of silica and asbestos. Inhaling
finely divided crystalline silica or asbestos dust Inflammasomes and Inflammation
in very small quantities over time can lead to in the Skin
inflammatory conditions known as silicosis and The skin is the body’s first line of de-
asbestosis, respectively (126). As the dust be- fense against external threats and serves as an

242 Martinon · Mayor · Tschopp

 ANRV371-IY27-09 ARI 16 February 2009 8:57
effective barrier against ordinary environmen-
tal intrusions. As such, the skin is often
damaged by various insults and proficient in
mounting efficient immune responses. Ultra-
violet irradiation, for example, was recently
shown to activate the NALP3 inflammasome
and promote IL-1β maturation in keratinocytes
(135). A role of the inflammasome in the skin
was also found in contact hypersensitivity, an
inflammatory disease caused by irritant chem-
icals that penetrate the skin surface and that
induce a T cell–mediated immune response
(136). This response is divided into two phases.
Annu. Rev. Immunol. 2009.27:229-265. Downloaded from arjournals.annualreviews.org
by Universidad Nacional Autonoma de Mexico on 03/24/09. For personal use only.
The first is a sensitization phase in which the
sensitizing chemical acts both as an adjuvant
and as a foreign hapten. Uptake of the chem-
ical by skin-resident antigen-presenting cells
(APCs) and their migration to draining lymph
nodes ensue, promoting T cell priming. Reex-
posure to the chemical defines a second phase,
also known as the elicitation phase. Here, chal-
lenge with the corresponding antigen triggers
the activation of primed T cells. The innate
immune module of the sensitization phase de-
pends on the presence of functional caspase-1,
IL-1β, and IL-18 (137–140), suggesting a po-
tential involvement of the inflammasome. The
role of the inflammasome was confirmed in
ASC- and NALP3-deficient mice that showed
an impaired contact hypersensitivity response
to the irritants trinitrophenylchloride (TNP-
Cl) (97), trinitrochlorobenzene (TNCB), and
dinitrofluorobenzene (DNFB) (141). In these
mice, transfer of primed T cells results in a
normal contact hypersensitivity, suggesting that
only the sensitization phase requires NALP3
and ASC. Interestingly, DNFB promotes the
release of IL-1β in a caspase-1-dependent man-
ner in primary keratinocytes as well as in a DC
line, suggesting that the inflammasome may ei-
ther detect such compounds directly or, more
likely, may detect some danger signals released
or produced by these irritants (142). On the
contrary, dinitrothiocanobenzene (DNTB) is
unable to activate the inflammasome and, as
such, fails to induce a strong immune response
in vivo despite the fact that DNTB is compe-
tent in inducing the effector phase if the re-
lated antigen DNFB (that activates the inflam-
masome) was used for sensitization (143). To-
gether, these findings suggest that the inflam-
Antigen-presenting
masome can bridge danger signals triggered by cells (APCs): cells
the irritant effect of sensitizing chemicals with that process antigens
the activation of IL-1β and IL-18, thus promot- and have special
ing efficient activation of the adaptive immune molecules (MHC) that
bind the processed
system.
antigens and display
them on the cell
surface for T cells to
ROS, the Common NALP3 Activator? recognize
Most danger signals described to activate the
NALP3 inflammasome trigger similar intracel-
lular changes that may converge on a common
mechanism of NALP3 activation (Figure 3).
Potassium efflux, the induction of frustrated
phagocytosis, and ROS production are the most
striking features associated with NALP3 acti-
vators (127). Large particles and crystals such
as MSU, alum, asbestos, and silica can induce
the so-called frustrated phagocytosis at the sur-
face of the cell, provoking the formation of
cytoskeletal filaments (144). Inhibition of cy-
toskeletal filament generation with the pharma-
cological agents cytochalasin D or colchicine
disrupts the ability of particles to trigger
IL-1β activation (8, 113, 127), suggesting that
the process of phagocytosis or frustrated phago-
cytosis is involved in NALP3 activation. In-
terestingly, colchicine (145) was one of the
first anti-inflammatory drugs identified for the
treatment of gout by the Greeks more than
fifteen centuries ago (146) and is still used in
modern medicine to treat inflammatory dis-
eases. ROS production occurs quickly upon ex-
posure of macrophages with silica or asbestos
dust (127, 128, 147, 148). Similarly, MSU and
alum produce ROS (113, 127). Both ATP and
the toxin nigericin (that do not require phago-
cytosis to activate the inflammasome) activate
ROS (149). A cellular redox imbalance also oc-
curs upon cellular stimulation with the skin
sensitizer DNCB, and ROS are also induced
by UV (150). Along this line, knockdown of
NAPDH subunits or the use of antioxidants
inhibit inflammasome activation induced by
alum, MSU, ATP, nigericin, asbestos, and silica
(93, 113, 127, 149). It is therefore reasonable to
www.annualreviews.org • The Inflammasomes 243
 ANRV371-IY27-09 ARI 16 February 2009 8:57

propose that ROS are either directly sensed
by NALP3 or indirectly sensed through cy-
toplasmic proteins that modulate inflamma-
Receptor for
advanced glycation some activity. ROS production by hydrogen
end product (RAGE): peroxide activates DCs in a similar way to
involved in the sensing TLRs (151) and activates the inflammasome
of HMGB1, a danger (127).
signal released by
ROS production is a well-known, highly
injured cells
conserved signal involved in damage and stress
sensing. ROS are also important players in in-
nate immune responses in plants (152). Ara-
bidopsis mutants that contain disruptions of
NADPH oxidases fail to generate a full ox-
Annu. Rev. Immunol. 2009.27:229-265. Downloaded from arjournals.annualreviews.org
by Universidad Nacional Autonoma de Mexico on 03/24/09. For personal use only.
(receptor for advanced glycation end product).
However, NLRs are localized in the cytosol
and thus are specialized in sampling PAMPs
and danger signals that ultimately reach or af-
fect this particular cellular compartment. Al-
though microbes may reach the cytosol of cells
during their life cycles, degradation products
from phagocytosed bacteria and viruses may
also be present in the cytosol and contribute
to NLR and inflammasome activation (154).
By definition, PAMPs represent molecules vi-
tal for microbial survival and are therefore un-
likely to vary in their structures because any

idative burst in response to infection by bac-
terial and fungal pathogens (48). Interestingly,
plant potassium efflux has been linked to ROS
production at the membrane (152). Potassium
efflux has also been implicated in NADPH
activation in granulocytes (153). It is therefore
possible that potassium efflux by NALP3 acti-
vators may be involved in ROS generation.
INFLAMMASOMES AS SENSORS
OF PATHOGENS
A key function of the innate immune sys-
tem is the recognition of invading microbes.
Responses to extracellular PAMPs and some
extracellular danger signals are mediated by
membrane receptors such as TLRs and RAGE
major change would be detrimental. Exam-
ples of PAMPs are bacterial structural com-
ponents, such as LPS and PGNs, or viral nu-
cleic acids. PAMPs are signatures that define
classes of microbes and, as such, are critical
in alerting the immune system. In addition to
detecting PAMPs, inflammasomes also detect
toxins and signals that are restricted to certain
pathogens (155) (Figures 3 and 4). It is tempt-
ing to hypothesize that these signals may or-
chestrate specific innate immune responses as
a result of a unique host-pathogen coevolution
maximizing fitness for both the pathogen and
the host. The pathogen may benefit from viru-
lence to promote spreading replication and sur-
vival, whereas the host evolves to cope with the
infection (156).

Virulence IPAF
factor Co-factors inflammasome
Pathogen
T3SS ? ASC
Shigella flexneri

T3SS
Salmonella typhimurium ASC
Flagellin
T3SS
Pseudomonas aeruginosa
IPAF
T4SS Flagellin NAIP5
Legionella pneumophila Caspase-1

Figure 4
Gram-negative pathogens secrete factors such as flagellin and possibly other virulence factors through type
III (T3SS) or type IV (T4SS) secretion systems to trigger an inflammasome dependent on caspase-1 and
IPAF. Genetic studies have demonstrated that caspase-1 activation in this context may also require the
adaptor ASC or the NOD-like receptor protein NAIP. Whether NAIP and ASC contribute to the formation
of IPAF inflammasomes directly or indirectly is unknown.

244 Martinon · Mayor · Tschopp

 ANRV371-IY27-09 ARI 16 February 2009 8:57
Inflammasome Activation by PAMPs
Inflammasomes respond to immunomodula-
tory PAMPs, mainly bacterial PGNs and nu-
cleic acids. PGNs are structural units of cell
walls common to all bacteria (157). Degrada-
tion of PGNs leads to the release of several
structural units including MDP. MDP is sensed
in the cytosol by the NLR NOD2, which ac-
tivates NF-κB. MDP also activates caspase-1
and IL-1β (158) via NALP3 in human mono-
cytes, suggesting that NALP3 is an additional
MDP sensor (69, 159, 160). The strength of
Annu. Rev. Immunol. 2009.27:229-265. Downloaded from arjournals.annualreviews.org
the immune response to MDP varies greatly
by Universidad Nacional Autonoma de Mexico on 03/24/09. For personal use only.
and depends on the animal species and genetic
background. Mice are much less sensitive than
humans, guinea pigs, or rats to these PGN-
derived peptides; moreover, C57BL/6 mice are
less sensitive than BALB/c mice (161, 162). In-
terestingly, both NF-κB and IL-1β activation
are greatly enhanced by MDP in the presence
of the protein synthesis inhibitor cycloheximide
(CHX), demonstrating that a CHX-sensitive
pathway may affect MDP internalization or its
presentation to NLRs (69). Genetic studies in
mice have shown that IL-1β activation by MDP
requires both NOD2 and NALP3, suggesting
that both these NLRs may cooperate either in-
directly or directly as part of the same molecular
complex (69). This finding is consistent with
the observation that monocytes from Crohn’s
disease patients who have functional mutations
in the NOD2 gene fail to activate IL-1β upon
MDP stimulation (163). Moreover, Muckle-
Wells patients that harbor a gain-of-function
mutation in the NALP3 gene overproduce
IL-1β upon stimulation with MDP (159). Sim-
ilarly, a probable gain-of-function mutation in
NOD2 in the mouse leads to increased IL-1β
production upon stimulation of macrophages
with MDP (164). NOD2 has also been sug-
gested to play a role, together with NALP1,
in MDP-induced caspase-1 activation, further
suggesting that multiple NLRs may cooperate
and synergize to mount host defenses (68, 165).
TLR9 and the intracellular protein DAI
have been identified as sensors for DNA result-
ing in the triggering of a type I IFN response
(166, 167). Similar to DAI, the inflammasome
is capable of sensing cytosolic DNA (168), al-
though this is unlikely to be direct. Infection
of a monocytic cell line or mouse macrophages
with adenoviruses and herpesviruses leads to ac-
tivation of caspase-1 and IL-1β. NALP3- and
ASC-deficient mice display reduced innate in-
flammatory responses to infection with aden-
ovirus. Inflammasome activation also occurs as
a result of transfected cytosolic bacterial, viral,
and mammalian (host) DNA; however, in this
case sensing is dependent on ASC only and not
on NALP3. It is also independent of TLRs and
IRFs (168). Studies have also identified RNA as
an activator of NALP3 (98, 169), although this
study could not be confirmed by other groups.
Pore-Forming Bacterial Toxins
Activate the NALP3 Inflammasome
Many bacterial pathogens produce toxins that
contribute to virulence by modifying host re-
sponses. Bacterial toxins are generally either
enzymes or pore-forming proteins (170). Most
of the bacterial toxins that activate NALP3
are pore-forming toxins. These toxins are re-
leased by bacteria in a soluble form and sub-
sequently polymerize into a ring-like structure
forming a pore in the membrane of the host
cell. Pore formation triggers ionic imbalance;
in particular, potassium efflux and calcium in-
fluxes are observed. These two processes are
common danger signals and are frequently as-
sociated with NALP3 inflammasome activation
(155). Among pore-forming toxins, α-toxin
from Staphylococcus aureus and aerolysin from
Aeromonas hydrophila are potent activators of the
NALP3 inflammasome (96, 171). Similarly, lis-
teriolysin O (LLO), a toxin released by Listeria
monocytogenesis, activates caspase-1 in an ASC-
and NALP3-dependent manner (96, 172).
Interestingly, ivanolysin O, a LLO-related cy-
tolysin that exhibits quite similar function re-
garding the contribution to the escape of
Listeria from the phagosome into the cytosol, is
unable to restore caspase-1 activation in LLO-
deficient strains, suggesting that these toxins
may engage specific signals beyond their ability
www.annualreviews.org • The Inflammasomes 245
 ANRV371-IY27-09 ARI 16 February 2009 8:57
to form pores (173). The release into the cytosol
of flagellin during Listeria infection activates the
IPAF inflammasome (but not the NALP3 in-
Virulence factor:
molecules produced by flammasome, see below), highlighting the abil-
pathogens that are ity of pathogens to engage specific and multiple
involved in host/ inflammasomes (174).
pathogen interaction
and aimed at
increasing the rate of Anthrax Lethal Toxin
infection
Activates NALP1
Bacillus anthracis is the causative agent of an-
thrax and depends for its virulence on the se-
cretion of factors that form functional toxins.
Annu. Rev. Immunol. 2009.27:229-265. Downloaded from arjournals.annualreviews.org
by Universidad Nacional Autonoma de Mexico on 03/24/09. For personal use only.
Anthrax lethal toxin (LeTx) is one of the major
toxins produced by B. anthracis and is believed
to be responsible for causing death in systemic
anthrax infections.
Macrophages from inbred mice are either
susceptible or resistant to cell death in response
to LeTx. This trait difference has been mapped
to a locus on chromosome 11 and is associ-
ated with a polymorphism in the nalp1b gene
that impinges on caspase-1 activation (175).
How LeTx activates NALP1 and the role of
the inflammasome in anthrax pathology are
still unknown. Murine NALP1b does not con-
tain a PYD; hence, it is not clear whether
it requires ASC or dimerization with another
NALP for caspase-1 recruitment. On the other
hand, NALP1b possesses a CARD and a region
related to CARDINAL. It is therefore possi-
ble that this CARD-containing region is able
to activate caspase-1 in an ASC-independent
manner, as was suggested for human NALP1
in vitro (26). Activation of caspase-1 by LeTx
requires binding, uptake, and endosome acidi-
fication to mediate translocation of lethal fac-
tor (a functional subunit of LeTx) into the host
cell cytosol. Interestingly, catalytically active
lethal factor activates caspase-1 by a mechanism
involving proteasome activity and potassium
efflux (176–178).
IPAF Inflammasome Activation
by Injected Virulence Factors
IPAF and NAIP5 have been involved in the
detection of virulence factors from Gram-
246 Martinon · Mayor · Tschopp
negative bacteria. Recognition of Salmonella ty-
phimurium and Shigella flexneri activates the
IPAF inflammasome that requires the ASC
adaptor (77, 179). The role of ASC in the IPAF
inflammasome is still unclear, but ASC may
stabilize or facilitate caspase-1 recruitment to
IPAF. Alternatively, IPAF may cooperate with a
yet to be defined NALP to activate caspase-1.
In contrast to S. typhimurium and S. flexneri,
Legionella pneumophila requires two murine
NLRs, NAIP5 and IPAF, for inflammasome
formation, but does not require ASC (180–
182). The role of NAIP5 in IPAF inflamma-
some activation is unknown. It has been sug-
gested that defective NAIP5 signaling ren-
ders macrophages permissive to L. pneumophila
despite caspase-1 activation, suggesting that
NAIP5 may have additional functions be-
yond its role in IPAF and caspase-1 acti-
vation (183). Unlike the seven NAIP genes
found in the murine genome, humans only
harbor one copy. Consistent with findings in
the mouse, knockdown of NAIP or IPAF in
human cell lines leads to enhanced suscepti-
bility to L. pneumophila (38). IL-18 produc-
tion and protection against Anaplasma phago-
cytophilum, a neutrophilic obligate bacteria that
causes human anaplasmosis, relies on ASC and
caspase-1 and partially on IPAF, but not on
NALP3 (184). Similarly, Pseudonomas aeruginosa
specifically activates the IPAF inflammasome
(185–187).
Most Gram-negative pathogens that acti-
vate IPAF require the type III secretion system
(T3SS) or the type IV secretion system (T4SS)
to inject into the host cell IPAF-activating vir-
ulence factors, mainly flagellin. These bacte-
rial injection machines span the two membranes
from the bacteria and the host cell membrane
(84). Polymers of flagellin form the flagella,
a structure anchored to the bacterial cell wall
that enables bacterial motility. Flagellin is a
well-known activator of host innate immunity
through its capacity to trigger TLR5 activation.
In this context, flagellin is considered a PAMP
as it is a vital, evolutionarily conserved ele-
ment of mobile bacteria. In the context of IPAF
activation, flagellin could be interpreted as a
 ANRV371-IY27-09 ARI 16 February 2009 8:57
virulence factor, as flagella formation is not re-
quired and flagellin release in the cytosol is
apparently the result of an active process de-
pendent on T3SS or T4SS injection systems
(84). Interestingly, S. flexneri, a pathogen that
does not have a flagellum and apparently does
not express flagellin, still requires the T3SS
for IPAF-induced caspase-1 activation, indicat-
ing that flagellin may not be the only T3SS
virulence factor used by pathogens to activate
IPAF inflammasomes (188). How flagellin or
other virulence factors engage IPAF inflamma-
somes as well as the precise function of ASC or
Annu. Rev. Immunol. 2009.27:229-265. Downloaded from arjournals.annualreviews.org
by Universidad Nacional Autonoma de Mexico on 03/24/09. For personal use only.
NAIP in detecting these signals and activating
caspase-1 are fascinating questions that need to
be solved in future studies.
INFLAMMASOME REGULATORS
Little is known about the mechanisms that reg-
ulate inflammasome activity. Inflammasome,
caspase-1, and IL-1β activation are best per-
formed in cells that express all the components
at high concentrations and in active forms. Most
cells do not express all the components re-
quired for inflammasome activation, necessitat-
ing prior stimulation or sensitization. THP-1
cells, for example, require differentiation of this
monocytic cell line into a macrophage-like cell
(70). Similarly, mouse macrophages are gen-
erally primed with LPS, and the response to
MDP may require incubation with the protein
synthesis inhibitor CHX (69). The pathogen
Francisella tularensis first triggers type I IFN ac-
tivation to enable ASC-dependent inflamma-
some activation (189). These experimental find-
ings hint of synergisms, feedback loops, and
checkpoints that ultimately control inflamma-
some activation and orchestrate the physiolog-
ical inflammatory response. Of particular inter-
est are negative feedback loops that are crucial
for the resolution phase of inflammation. NF-
κB for example, a well-known proinflamma-
tory transcription factor, is also a crucial player
in the down-modulation of the inflammatory
response including inflammasome activation
(190). Although we know little at the physio-
logical level, investigators have identified vari-
ous proteins that may interfere with inflamma-
some assembly and inflammatory caspase acti-
vation. Based on the modular structure of these
proteins, we can distinguish two major types
of inflammasome regulators: those containing
a CARD domain and those with a PYD domain
(Figure 5).
Pyrin Domain–Containing
Inflammasome Regulators
PYD-containing regulators are believed to in-
terfere with PYD-PYD interaction between
NALPs and the adaptor ASC. These PYD reg-
ulators include Pyrin, POP1, POP2, and viral
PYDs (vPYDs). POPs and the poxviral gene
product M13L-PYD (also known as vPYD)
are short proteins that contain mainly a PYD
(191). Poxviruses deficient in vPYD produce
an enhanced activation of caspase-1 and secre-
tion of IL-1β, further strengthening the idea
that inflammasomes (that sense viral DNA) are
important players in immunity against viruses
(192–194). Similarly, POP1 and POP2 mod-
ulate inflammasome activity probably by dis-
rupting ASC-NALP interactions (191, 195).
The absence in the mouse genome of both
POP1 and POP2 makes the evaluation of their
physiological importance in vivo challenging.
Pyrin was initially identified as the product
of the MEFV gene, which is mutated in pa-
tients with familial Mediterranean fever (FMF)
(196), a hereditary autoinflammatory syndrome
characterized by episodic fever and serosal or
synovial inflammation. Targeted disruption of
Pyrin in mice causes increased endotoxin sensi-
tivity and enhanced caspase-1 activation (197).
Most of the mutations in Pyrin in FMF pa-
tients affect the C terminus, which harbors a
PRY-SPRY domain. The function of this do-
main, which is partially absent in the mouse,
is not clear, but a role in the regulation of
the inflammasome and caspase-1 was proposed
(55, 56, 197). The PYD of Pyrin interacts
with the PYD of ASC (197), suggesting that it
may be involved in blocking the recruitment of
ASC and inflammasome formation. However,
artificial overexpression of Pyrin can also be
www.annualreviews.org • The Inflammasomes 247
 ANRV371-IY27-09 ARI 16 February 2009 8:57

NALP3 IPAF
inflammasome inflammasome

Pyrin
POP1, POP2
vPYDs
Bcl-2
NALP3
Bcl-XL
IPAF

Caspase-1
ASC
Caspase-1
Annu. Rev. Immunol. 2009.27:229-265. Downloaded from arjournals.annualreviews.org

PYD
by Universidad Nacional Autonoma de Mexico on 03/24/09. For personal use only.

CARD
Caspase-12
PRY-SPRY
BBox Iceberg
Pi9, vCrmA, Pseudo-ICE
Flightless-I INCA

Figure 5
Inflammasome activity is inhibited by PYD-containing proteins that interfere with ASC and NALP
interaction and CARD-containing proteins that disrupt caspase-1 interaction with IPAF or ASC. Bcl-2 and
Bcl-XL proteins have been suggested to inhibit NALP oligomerization (165). Caspase-1 activity can be
directly blocked by Flightless-I (259), and the serpin protease inhibitor 9 (Pi9) (260) or cowpox
virus-encoded inhibitor of caspase-1, vCrmA (261).

proinflammatory. This led Fernandes-Alnemri CARD Domain-Containing

et al. (198) to propose an alternative hypoth-
esis, namely that Pyrin, like NALP3, assem-
bles an inflammasome with ASC and caspase-1.
On the other hand, FMF is mainly considered
to be an autosomal recessive autoinflamma-
tory disorder, an observation more consistent
with the notion that Pyrin loss-of-function may
cause the aberrant inflammation in these pa-
tients by allowing inflammasome hyperactiva-
tion (199). PSTPIP1, a Pyrin-interacting pro-
tein, is mutated in PAPA syndrome (pyogenic
arthritis, pyoderma gangrenosum, and acne), an
autoinflammatory disease associated with over-
production of IL-1β (200). Moreover, muta-
tions in a mouse-related protein, PSTPIP2,
cause a macrophage-dependent autoinflamma-
tory syndrome, further delineating the im-
portance of Pyrin and inflammasome regula-
tion in autoinflammatory disorders (201, 202)
(see below).
Regulators
A small family of inflammasome regulators
harbor a CARD that is highly similar to the
CARD of caspase-1. These proteins most likely
emerged from successive gene duplications and
include in humans iceberg, INCA, COP, and
caspase-12 (33, 203, 204). Through CARD-
CARD interactions these proteins presumably
inhibit processing of proIL-1β by preventing
recruitment and/or activation of the caspase by
the adaptor ASC or IPAF. Except for caspase-
12, most of these proteins are not present in
the mouse or rat genomes, again highlighting
considerable differences in the regulation of
the inflammasome in diverse species. Caspase-
12 is present in two main polymorphic vari-
ants in human, resulting in the production of
either a truncated protein containing the N-
terminal CARD domain (CARD-only) or a full-
length variant molecule (caspase-12L) (205).

248 Martinon · Mayor · Tschopp

 ANRV371-IY27-09 ARI 16 February 2009 8:57
The full-length variant of caspase-12, which is
the less frequent allele, confined to the popu-
lation of African descent, is linked to hypore-
sponsiveness to LPS-induced production of
cytokines (205, 206). Genetic studies have pre-
dicted that the polymorphism generating the
caspase-12 short variant was driven by posi-
tive selection to complete fixation in the human
genome approximately 60,000–100,000 years
ago (207, 208). Loss of the caspase-12 C ter-
minus may have conferred a selective bene-
fit, possibly by increasing sepsis resistance in
human populations that experienced emergent
Annu. Rev. Immunol. 2009.27:229-265. Downloaded from arjournals.annualreviews.org
by Universidad Nacional Autonoma de Mexico on 03/24/09. For personal use only.
infectious diseases as geographic expansion oc-
curred in association with increases in human
population size and density. In line with this
hypothesis, caspase-12-deficient mice clear
bacterial infection more efficiently than do
wild-type littermates and have an enhanced
production of proinflammatory cytokines, in-
cluding IL-1β and IL-18 (209). Caspase-12 was
proposed to be a decoy caspase that blocks
caspase-1 activation resulting in enhanced vul-
nerability to bacterial infection and septic mor-
tality, similar to cFLIP (a decoy caspase-8-like
protein), which regulates caspase-8-mediated
apoptosis. However, contrary to FLIP, the full-
length variant of caspase-12 has autoproteolytic
activities, a mechanism that may regulate its
anti-inflammasome properties or may under-
line the possibility that the full-length variant
of caspase-12 cleaves specific substrates yet to
be identified (210).
INFLAMMASOME SIGNALING
AND DISEASE ASSOCIATIONS
Although inflammasomes are involved in both
pathways of pathogen and danger signal sens-
ing, their function converges in the activation
of inflammatory caspases (mainly caspase-1),
which have few known substrates, primarily IL-
1β, IL-18, and possibly IL-33. The complex-
ity of inflammasome assembly contrasts with
the reductionist vision of its main role as a
trigger of IL-1β and IL-18 maturation. More-
over, IL-1β, IL-18, and IL-33 are related cy-
tokines that initiate a MyD88-dependent sig-
naling pathway, very similar to the pathway
engaged by TLRs. Therefore, pathogen sens-
ing by inflammasomes can be interpreted as
an indirect activation of a TLR-like receptor
(IL-1R or IL-18R), a scenario that is compa-
rable to the activation mechanism of the Toll
receptor in Drosophila (19). Both mammalian
and Drosophila signaling pathways involve the
activation of, in mammals, cytokines IL-1β
and IL-18 and, in Drosophila, Spätzle through
proteolytic processing, which is initiated by
microbial sensors that engage and activate spe-
cific proteases. Although IL-1-processing in-
flammasomes in mammals sense pathogens in
the cytosol, the proteases that activate Spätzle
are localized and activated in the hemolymph
of the fruit fly. With this in mind, the complex-
ity and diversity of inflammasomes may reflect
the multitude of pathogens and danger signals
that are detected in specific locations, whereas
the conservation of TLRs and IL-1β/IL-18 re-
ceptor signaling cascades emphasizes the im-
portance of MyD88 signaling in innate immu-
nity (19). The discovery of specific activators
that signal through an inflammasome-IL-1β
pathway brought new interest to the biology of
IL-1β. As new caspase-1 substrates are being
uncovered, new inflammasome functions will
emerge beyond its role in the maturation of
IL-1β, IL-18, and possibly IL-33 (171, 211–
213).
Inflammasomes, Inflammation,
and Inflammatory Diseases
Originally identified as the endogenous py-
rogen, exogenous IL-1β triggers fever in ex-
perimental animals (214). In addition to fever,
IL-1β has multiple other effects on the cen-
tral nervous system. These include induction
of slow-wave sleep, anorexia, and inflammatory
pain hypersensitivity, typically associated with
infections or injury (214, 215). The important
role of IL-1β and the inflammasome in inflam-
mation and fever is strongly supported by ge-
netic evidence that links the inflammasome to
www.annualreviews.org • The Inflammasomes 249
 ANRV371-IY27-09 ARI 16 February 2009 8:57

Table 2 Diseases associated with inflammasome activity

Gene Etiologic Inflammasome Anakinra
Disease Clinical features mutated agent involvement response
Familial cold Fever, arthralgia, NALP3 overactive yes
autoinflammatory cold-induced urticaria
syndrome (FCAS)
Muckle-Wells syndrome Fever, arthralgia, urticaria, NALP3 overactive yes
(MWS) sensorineural deafness,
amyloidosis
Chronic infantile Fever, severe arthralgia, NALP3 overactive yes
neurological cutaneous and urticaria, neurological
articular syndrome problems, severe
(CINCA, NOMID) amyloidosis
Annu. Rev. Immunol. 2009.27:229-265. Downloaded from arjournals.annualreviews.org

Familial Mediterranean Fever, peritonitis, pleuritis, Pyrin overactive partial

by Universidad Nacional Autonoma de Mexico on 03/24/09. For personal use only.

fever (FMF) amyloidosis

Pyogenic arthritis, pyoderma Pyogenic sterile arthritis PSTPIP1 overactive yes
gangrenosum, and acne
syndrome (PAPA)
Hyperimmunoglobulin D Arthralgia, abdominal pain, Mevalonate to be demonstrated yes
syndrome (HIDS) lymphadenopathy kinase
Tumor necrosis factor Fever, abdominal pain, skin TNF-R1 to be demonstrated yes
receptor-1-associated lesions
syndrome (TRAPS)
Systemic juvenile idiopathic Chronic joint inflammation unknown to be demonstrated yes
arthritis (SOJIA)
Adult-onset Still’s disease Arthralgia, fever unknown to be demonstrated yes
(AOSD)
Behcet’s disease Arthralgia, uveitis, ulcers unknown to be demonstrated yes
Schnitzler’s syndrome Urticaria, fever arthralgia unknown to be demonstrated yes
Gout Metabolic arthritis, pain uric acid activated yes
(MSU)
Pseudogout Arthritis CPPD activated yes
Contact dermatitis Urticaria irritants activated unknown
Fever syndrome Fever NALP12 unknown unknown
Hydatidiform mole Hydatid mole NALP7 unknown unknown
Vitiligo Skin depigmentation, NALP1 unknown unknown
automimmunity

a family of hereditary periodic fevers (HPFs)
(216) (Table 2). HPFs are heritable disor-
ders characterized by unexplained and recur-
rent episodes of fever and severe inflamma-
tion. These patients suffer from rashes and
serosal and synovial inflammation with vary-
ing degree of neurological involvement. HPFs
are part of the expanding family of so-called
autoinflammatory diseases that differ from au-
toimmune disorders in that evidence for adap-
tive immunity components such as autoreac-
tive T cells or immunoglobulins to self-antigens
is lacking (217). Familial cold autoinflamma-
tory syndrome (FCAS), Muckle-Wells syn-
drome (MWS), and chronic infantile cutaneous
neurological articular syndrome (CINCA), also
termed neonatal-onset multisystem inflamma-
tory disease (NOMID), are all caused by

250 Martinon · Mayor · Tschopp

 ANRV371-IY27-09 ARI 16 February 2009 8:57

mutations in the third exon of NALP3 (218, Inflammasomes, Adjuvanticity,

219). These diseases have overlapping charac- and Autoimmune Diseases
teristics and form a clinical continuum. FCAS
Adjuvants are materials that enhance the im-
patients have the less severe symptoms that gen-
mune response to an antigen. Several different
erally include fever (often triggered by tem-
types of adjuvants exist, ranging from mineral
perature changes), arthralgia, and skin rashes.
salts such as alum to oil-based emulsions such
MWS patients may, in addition, develop amy-
as incomplete Freund’s adjuvant. On a molecu-
loidosis together with deafness. NOMID pa-
lar basis, adjuvants are believed to boost antigen
tients have the most severe symptoms that
presentation by APCs such as macrophages or
may lead to very serious neurological impair-
DCs. More efficient antigen presentation can
ment caused by chronic polymorphonuclear
be achieved by adding, for example, TLR ag-
meningitis. The disease-causing mutations in
onists, which activate the APCs, promote the
MWS, NOMID, and FCAS are believed to
Annu. Rev. Immunol. 2009.27:229-265. Downloaded from arjournals.annualreviews.org

upregulation of costimulatory molecules, im-

by Universidad Nacional Autonoma de Mexico on 03/24/09. For personal use only.

confer gain-of-function to NALP3 leading to

prove antigen presentation, and enhance cy-
a hyperactive inflammasome. Consistent with
tokine induction. Unfortunately, TLR agonists
this model, increased secretion of IL-1β is
may be too toxic to be used in human vac-
observed in macrophages from patients with
cines; moreover, immune responses to an anti-
disease-associated NALP3 mutations (78, 220).
gen can also occur in the absence of TLR sig-
Moreover, overexpression of mutant NALP3
naling (227). Similar to TLR agonists, IL-1β
proteins induces spontaneous IL-1β secretion
has adjuvant properties. When mice are im-
(221). IL-1β is therefore the likely major me-
munized with protein antigens together with
diator of inflammation in this disease. This
IL-1β, serum antibody production is enhanced.
model is supported by studies demonstrating
In humans, IL-1 also promotes the expansion of
that treatment of these patients with an in-
IL-17-secreting memory CD4+ T cells (228,
hibitor of IL-1 (IL1-ra) leads to a very striking
229). Interestingly, many of the inflammasome
and dramatic improvement of symptoms in all
activators have adjuvant properties; these in-
three conditions (222–225).
clude MDP [whose role in enhancing immune
Genes responsible for other autoinflamma-
responses has been known for more than three
tory diseases may also be linked to inflam-
decades (230)], MSU (111), and alum (131).
masome activity (Table 2). FMF is an HPF
Alum defines particle materials based on alu-
characterized by recurrent inflammation of
minum salt precipitates that are the most widely
serosal surfaces and is associated with muta-
used adjuvants in human vaccines. Alum ac-
tions in the PYD-containing inflammasome
tivates a Th2-biased immunity with elevated
regulator Pyrin (220). The inflammatory dis-
Th2-dependent antibody isotypes IgG1 and
ease PAPA is another condition in which im-
IgE (131). Similar to MSU, alum triggers an
paired IL-1β regulation is caused by mutations
influx of neutrophils when injected in vivo, and
in PSTPIP1(CD2BP), a protein that binds to
both have similar adjuvant properties result-
Pyrin and may be involved in scaffolding in-
ing (in presence of an antigen) in an efficient
flammasome components to the cytoskeleton
adaptive immune response (8, 113, 117). Im-
(200). Other autoinflammatory diseases such as
portantly, both MSU and alum depend on an
gout, pseudogout, silicosis, and asbestosis are
intact inflammasome including NALP3, ASC,
associated with aberrant activation of NALP3.
and caspase-1 to trigger a Th2-biased response
In these cases, aberrant inflammasome activa-
(113, 117, 119). Similarly, silicosis triggered by
tion is not caused by an inherited mutation in
silica dust (another NALP3 activator) is also
inflammasome components or regulators, but
characterized by a Th2 response (231). These
by chronic exposure to inflammasome activa-
findings demonstrate the importance of the
tors such as MSU, CPPD, and inflammation-
inflammasome in linking innate immunity to
inducing dust (226).

www.annualreviews.org • The Inflammasomes 251

 ANRV371-IY27-09 ARI 16 February 2009 8:57

Cytokines
Alum
?
Antigen IL-1β
IL-18
Cytokines IL-33

IL-1β Inflammasome 2
IL-18 1
IL-33?
? ANTIG EN
PRES ENTING B CELL
CELL 3 An
ti
MHgen-
C
Annu. Rev. Immunol. 2009.27:229-265. Downloaded from arjournals.annualreviews.org
by Universidad Nacional Autonoma de Mexico on 03/24/09. For personal use only.

Cos
t
mo imula
lec tory
ule
s T CELL
Th2 cytokines

Figure 6
Model of inflammasome-mediated adjuvanticity. Antigen-presenting cells (APCs) can sense antigens
(contained within adjuvants, such as alum) through the inflammasome. Inflammasome activation leads to the
release of caspase-1-dependent cytokines including IL-1β, IL-18, and IL-33, which may in an autocrine
manner trigger their respective receptors to promote antigen presentation, upregulation of costimulatory
molecules, and the release of cytokines, which ultimately result in the stimulation of antigen-specific T and B
cells (1). Secreted IL-1β, IL-18, and possibly IL-33 may also directly contribute to the activation of T and B
cells (2). The question marks illustrate the possibility that the inflammasome may activate an as yet
unidentified factor that would signal in a MyD88-independent manner. This could explain the observation
that inflammasome-mediated adjuvanticity is MyD88-independent. Yet to be identified substrates and
signaling pathways linked to the inflammasome may also directly enhance costimulatory signals (3).

adaptive immunity. A critical question that re-
mains to be addressed is how the inflammasome
initiates lymphocyte activation and how it fa-
vors Th2 immunity (Figure 6). The three cy-
tokines that we know to depend for activity on
the NALP3 inflammasome are IL-1β, IL-18,
and possibly IL-33, which are all known to trig-
ger various aspects of Th2 immune responses.
For example, IL-1 is crucial in regulating Th2
responses during gastrointestinal nematode in-
fection (232) and was suggested more than
20 years ago as mediating Th2 responses upon
immunization with an antigen in alum (133).
IL-33 induces the expression of IL-4, IL-5, and
IL-13 and mediates Th2 polarization by en-
gaging the ST2 receptor (233). IL-18, which
is commonly considered to promote Th1 im-
munity, can amplify Th2 responses and pro-
mote Th2-biased pathologies, such as asthma,
by triggering the production of IgE antibodies
(234). These observations strongly suggest that
the inflammasome-generated cytokines play a
role in the adjuvant properties of alum and
MSU. Surprisingly, no defect in alum ad-
juvanticity was observed in MyD88-deficient
mice (113, 227). MyD88 is a crucial signal-
ing molecule downstream of IL-1 and IL-18.
Moreover, MyD88 is downstream of IL-33,
suggesting that all three cytokines may not
be directly involved in regulating the ad-
juvant properties of alum, or that MyD88-
independent signals, triggered by ST2 or other
IL-1R family members, are involved in this pro-
cess. New inflammasome and caspase-1 sub-
strates have recently been identified, but the
role of these proteins in regulating immune re-
sponses remains to be investigated in the con-
text of antigen immunization (171, 211–213).

252 Martinon · Mayor · Tschopp

 ANRV371-IY27-09 ARI 16 February 2009 8:57
The role of inflammasomes in regulating the
adaptive immune response is supported by
the findings showing that polymorphisms in
NALP1 are associated with vitiligo-associated
multiple autoimmune disease (235), a disor-
der in which the patients, in addition to gen-
eralized vitiligo characterized by loss of skin
pigments, have increased frequency of several
other autoimmune diseases, particularly au-
toimmune thyroid disease, latent autoimmune
diabetes, rheumatoid arthritis, psoriasis, per-
nicious anemia, systemic lupus erythematosus,
and Addison’s disease.
Annu. Rev. Immunol. 2009.27:229-265. Downloaded from arjournals.annualreviews.org
by Universidad Nacional Autonoma de Mexico on 03/24/09. For personal use only.
Ironically, although the role of the inflam-
masome in promoting the adaptive immune
response and in autoimmunity is now widely
accepted, most of the diseases with established
inflammasome overactivation lead to autoin-
flammatory syndromes that, by definition, are
devoid of autoreactive T cells and autoreactive
antibodies. A better understanding of the role of
the various inflammasome mediators in the reg-
ulation of the inflammatory (innate) response
and the adaptive response may help to solve this
paradox.
Inflammasomes and Pyroptosis
Under certain conditions, activation of in-
flammasomes, and thus inflammatory caspases,
leads to cell death. The word pyroptosis—
which is derived from the Greek “pyro” (fire),
to denote the release of proinflammatory me-
diators, and “ptosis,” which in Greek means
falling, a term commonly used to describe cell
death—was introduced for this particular type
of cell death (236). Pyroptosis is dependent
on the activation of caspase-1, is often asso-
ciated with a high inflammatory state in con-
trast to the silent apoptotic death, and fre-
quently occurs upon infection with intracellular
pathogens. It has been best studied in the con-
text of Shigella-infected macrophages. S. flexneri
is a human intestinal pathogen, causing dysen-
tery by invading the epithelium of the colon.
This facultative intracellular pathogen evades
the phagosome to enter the cytosol where it
can trigger cell death (237). Shigella-induced
macrophage death requires the inflammatory
caspase-1, but not the apoptotic caspase-3 (238,
239). Similarly, caspase-1-dependent cell death
Pyroptosis: a form of
has been reported in macrophages infected cell death associated
with Salmonella typhimurium (240), Pseudomonas with antimicrobial
aeruginosa (186), Francisella tularensis (241), responses during
Legionella pneumophila (180), and Listeria mono- inflammation and
dependent on the
cytogenes (242).
activation of an
Surprisingly, inflammasome requirements inflammasome and
differ between caspase-1-dependent IL-1β and inflammatory caspases
IL-18 secretion and pyroptosis. Both IPAF such as caspase-1
and ASC are required for cytokine produc-
tion by Salmonella-infected macrophages; how-
ever, only IPAF-deficient macrophages are
completely resistant to Salmonella-induced py-
roptosis, whereas ASC-deficient macrophages
are only partially protected (77). Similarly,
S. flexneri and P. aeruginosa require both IPAF
and ASC to induce IL-1β secretion, whereas
ASC is dispensable for triggering pyroptosis
(186–188). In the case of Bacillus anthracis, the
causative agent of anthrax, pyroptosis depends
on NALP1 (176, 243). These findings are in
contradiction with an in vitro study propos-
ing that pyroptosis is triggered by an ASC-
dependent, but NALP-independent, complex
(termed pyroptosome) (198, 244). Overall,
these studies support a model whereby ASC
as well as NALP and IPAF inflammasomes
form distinct complexes, possibly with differ-
ent cellular localization or different substrate
specificity. Detailed biochemical studies are re-
quired to shed some light on the various types
of inflammasomes formed upon infection of
macrophages with live pathogens. It is notewor-
thy that ASC-dependent inflammasome activa-
tion leads to a very rapid secretion of inflamma-
tory caspases including caspase-1 and caspase-5
(70). It is therefore tempting to postulate that
the rapid secretion of the inflammatory caspases
may be part of a regulatory mechanism aimed
at reducing cell death associated with ASC and
NALP inflammasomes.
Emerging Inflammasome Functions
Studies on IL-1 and inflammatory caspases
have recently highlighted the role of these
www.annualreviews.org • The Inflammasomes 253
 ANRV371-IY27-09
Annu. Rev. Immunol. 2009.27:229-265. Downloaded from arjournals.annualreviews.org
by Universidad Nacional Autonoma de Mexico on 03/24/09. For personal use only.
ARI 16 February 2009 8:57
inflammatory mediators in pathways and
pathologies that may involve inflammasome
activation, including neurodegenerative disor-
ders, cancer, and fertility-associated conditions
(245–247).
IL-1 is a key mediator of experimentally in-
duced neurodegeneration, and its inhibition is
neuroprotective in vitro and in vivo (246, 248).
Interestingly, NAIP (a NLR associated with
the IPAF inflammasome) is partially deleted
in individuals with the neurodegenerative dis-
ease spinal muscular atrophy (249). The fib-
rillar peptide amyloid-β has a key function in
the pathogenesis of Alzheimer’s disease (250).
Similar to uric acid crystals, the phagocytosis
of amyloid-β was found to activate the NALP3
inflammasome and to be critical for the recruit-
ment of microglia to exogenous amyloid-β in
the brain. Thus, the activation of the NALP3
inflammasome may be important for inflamma-
tion and tissue damage in Alzheimer’s disease.
IL-1β is known to play a role in both ovula-
tion and oocyte maturation (251). In the mare,
intrafollicular injection of IL-1β leads to in-
creased ovulation, but also to a very low rate
of embryo development, most likely owing to
a defect in oocyte maturation (252). Similarly,
IL-1β perfusion in the rabbit ovary blocks em-
bryo development at the four-cell stage (253).
It is therefore possible that inflammasomes may
link some aspects of innate immunity to re-
productive biology. Indeed, the expression pro-
files of NALP4, NALP5, NALP8, and NALP9
in gametes and preimplantation embryos, to-
gether with genetic studies, suggest a possi-
ble function for these proteins in the biology
of reproduction (33). NALP5 (Mater)-deficient
female mice are sterile owing to an arrest
at the two-cell stage in the development of
the embryos (254). Furthermore, mutations in
NALP7 cause recurrent hydatidiform moles,
an abnormal human pregnancy with no em-
bryo and cystic degeneration of placental villi
in humans (255–257). Although it is known that
inflammation and bacterial infection cause in-
fertility, ectopic pregnancy, and abortion, the
role of NALP7 in this disease is unknown. Sim-
ilarly, the ability of NALP7, as well as many
254 Martinon · Mayor · Tschopp
other NALPs, to form inflammasomes simi-
lar to the NALP3 inflammasome has not been
investigated.
CONCLUDING REMARKS
In the past decade, our understanding of the cel-
lular and molecular mechanisms by which the
innate immune system molecules sense specific
molecular patterns from components of invad-
ing organisms of both bacterial and viral ori-
gin has increased tremendously. The NLRs, to-
gether with the TLRs, are now appreciated to
be part of this important sensing system that
allows the host to mount an effective immune
response for elimination of the microbe and for
establishment of an effective adaptive immune
response for long-lasting immunity. What is
fascinating is the realization that at least one
NLR member, NALP3, a receptor that was pos-
tulated more than 10 years ago, also detects
various endogenous, sterile danger signals in
the absence of microbial infections. Danger sig-
nals include several particles such as uric acid
crystals, asbestos, or aluminum, which cause
the assembly of the NALP3 inflammasome and
the generation of the proinflammatory cytokine
IL-1. The remarkable progress in this field of-
fers new hope for many patients. We can antici-
pate a new generation of IL-1 antagonists in the
near future. A new IL-1β antibody is currently
in Phase II trials for rheumatoid arthritis, and
various inflammatory diseases, such as gout, are
now successfully treated with an IL-1 inhibitor.
Moreover, the efficiency of aluminum as an ad-
juvant can now be explained at the molecular
level and may help to design effective, but safe,
adjuvants in the future.
Yet despite our increased knowledge, many
questions remain. The precise roles and needs
for molecules such as IPAF and NAIP remain
ill defined. The ligands of many other NLRs
are unknown and their functions elusive. Al-
though mutations in NOD2 and NALP3 genes
provide a basis for susceptibility to Crohn’s dis-
ease and inflammatory diseases, why is a muta-
tion in NALP1 associated with vitiligo? What is
the significance of proteins other than IL-1 and
 ANRV371-IY27-09 ARI 16 February 2009 8:57

IL-18 cleaved by the inflammasome-activated
caspase-1, such as caspase-7 or enzymes of the
glycolytic pathway (258)?
From what we have learned about the func-
tion of NLRs in the short time since their dis-
covery, it is obvious that a future better un-
derstanding of the biology of NLRs will not
only help to elucidate their role in host re-
sponses to infectious agents and to danger sig-
nals, but will certainly contribute to the devel-
opment of desperately needed novel types of
anti-inflammatory drugs.

DISCLOSURE STATEMENT
The authors are not aware of any affiliations, memberships, funding, or financial holdings that
might be perceived as affecting the objectivity of this review.
Annu. Rev. Immunol. 2009.27:229-265. Downloaded from arjournals.annualreviews.org

ACKNOWLEDGMENTS
by Universidad Nacional Autonoma de Mexico on 03/24/09. For personal use only.

We thank members of the Tschopp lab for comments and discussions and Mirjam Eckert for
critically reviewing the manuscript.

LITERATURE CITED
1. Basset C, Holton J, O’Mahony R, Roitt I. 2003. Innate immunity and pathogen-host interaction. Vaccine
21(Suppl. 2):S12–23
2. Medzhitov R, Janeway CA. 1997. Innate immunity: impact on the adaptive immune response. Curr. Opin.
Immunol. 9:4–9
3. Medzhitov R, Janeway CA. 2002. Decoding the patterns of self and nonself by the innate immune system.
Science 296:298–300
4. Janeway CA. 1992. The immune system evolved to discriminate infectious nonself from noninfectious
self. Immunol. Today 13:11–16
5. Matzinger P. 2002. The danger model: a renewed sense of self. Science 296:301–5
6. Seong SY, Matzinger P. 2004. Hydrophobicity: an ancient damage-associated molecular pattern that
initiates innate immune responses. Nat. Rev. Immunol. 4:469–78
7. Ishii KJ, Suzuki K, Coban C, Takeshita F, Itoh Y, et al. 2001. Genomic DNA released by dying cells
induces the maturation of APCs. J. Immunol. 167:2602–7
8. Martinon F, Pétrilli V, Mayor A, Tardivel A, Tschopp J. 2006. Gout-associated uric acid crystals 8. Shows that large
activate the NALP3 inflammasome. Nature 440:237–41 particles of uric acid
9. Medzhitov R. 2008. Origin and physiological roles of inflammation. Nature 454:428–35 (urate) crystals induce
10. Kawai T, Akira S. 2007. TLR signaling. Semin. Immunol. 19:24–32 inflammation by
11. O’Neill LA, Bowie AG. 2007. The family of five: TIR-domain-containing adaptors in Toll-like receptor activating the NALP3
inflammasome.
signalling. Nat. Rev. Immunol. 7:353–64
12. Gay NJ, Gangloff M. 2007. Structure and function of Toll receptors and their ligands. Annu. Rev. Biochem.
76:141–65
13. Yoneyama M, Kikuchi M, Natsukawa T, Shinobu N, Imaizumi T, et al. 2004. The RNA helicase RIG-I
has an essential function in double-stranded RNA-induced innate antiviral responses. Nat. Immunol.
5:730–37
14. Sumpter R, Loo YM, Foy E, Li K, Yoneyama M, et al. 2005. Regulating intracellular antiviral defense
and permissiveness to hepatitis C virus RNA replication through a cellular RNA helicase, RIG-I. J. Virol.
79:2689–99
15. Andrejeva J, Childs KS, Young DF, Carlos TS, Stock N, et al. 2004. The V proteins of paramyx-
oviruses bind the IFN-inducible RNA helicase, mda-5, and inhibit its activation of the IFN-β promoter.
Proc. Natl. Acad. Sci. USA 101:17264–69
16. Meylan E, Curran J, Hofmann K, Moradpour D, Binder M, et al. 2005. Cardif is an adaptor protein in
the RIG-I antiviral pathway and is targeted by hepatitis C virus. Nature 437:1167–72

www.annualreviews.org • The Inflammasomes 255

 ANRV371-IY27-09 ARI 16 February 2009 8:57

17. Johnson CL, Gale M. 2006. CARD games between virus and host get a new player. Trends Immunol.
27:1–4
18. Seth RB, Sun L, Ea CK, Chen ZJ. 2005. Identification and characterization of MAVS, a mitochondrial
antiviral signaling protein that activates NF-κB and IRF 3. Cell 122:669–82
19. Martinon F, Tschopp J. 2005. NLRs join TLRs as innate sensors of pathogens. Trends Immunol. 26:447–54
20. Kufer T, Fritz JH, Philpott DJ. 2005. NACHT-LRR proteins (NLRs) in bacterial infection and immu-
nity. Trends Microbiol. 13:381–88
21. Bella J, Hindle KL, McEwan PA, Lovell SC. 2008. The leucine-rich repeat structure. Cell Mol. Life Sci.
65(15):2307–33
22. Liu L, Botos I, Wang Y, Leonard JN, Shiloach J, et al. 2008. Structural basis of Toll-like receptor 3
signaling with double-stranded RNA. Science 320:379–81
23. Brodsky I, Medzhitov R. 2007. Two modes of ligand recognition by TLRs. Cell 130:979–81
24. Leipe DD, Koonin EV, Aravind L. 2004. STAND, a class of P-loop NTPases including animal and plant
Annu. Rev. Immunol. 2009.27:229-265. Downloaded from arjournals.annualreviews.org

regulators of programmed cell death: multiple, complex domain architectures, unusual phyletic patterns,
by Universidad Nacional Autonoma de Mexico on 03/24/09. For personal use only.

and evolution by horizontal gene transfer. J. Mol. Biol. 343:1–28

25. Martinon F, Tschopp J. 2004. Inflammatory caspases: linking an intracellular innate immune system to
autoinflammatory diseases. Cell 117:561–74
26. Faustin B, Lartigue L, Bruey JM, Luciano F, Sergienko E, et al. 2007. Reconstituted NALP1 inflamma-
some reveals two-step mechanism of caspase-1 activation. Mol. Cell 25:713–24
27. Park HH, Lo YC, Lin SC, Wang L, Yang JK, Wu H. 2007. The death domain superfamily in intracellular
signaling of apoptosis and inflammation. Annu. Rev. Immunol. 25:561–86
28. Aravind L, Dixit VM, Koonin EV. 2001. Apoptotic molecular machinery: vastly increased complexity in
vertebrates revealed by genome comparisons. Science 291:1279–84
29. Tschopp J, Martinon F, Burns K. 2003. NALPs: a novel protein family involved in inflammation. Nat.
Rev. Mol. Cell Biol. 4:95–104
30. Inohara N, Nuñez G. 2003. NODs: intracellular proteins involved in inflammation and apoptosis. Nat.
Rev. Immunol. 3:371–82
31. Lich JD, Ting JP. 2007. CATERPILLER (NLR) family members as positive and negative regulators of
inflammatory responses. Proc. Am. Thoracic Soc. 4:263–66
32. Proell M, Riedl S, Fritz J, Rojas A, Schwarzenbacher R. 2008. The Nod-like receptor (NLR) family: a
tale of similarities and differences. PLoS ONE 3:e2119
33. Martinon F, Tschopp J. 2007. Inflammatory caspases and inflammasomes: master switches of inflamma-
tion. Cell Death Differ. 14:10–22
34. Reith W, Mach B. 2001. The bare lymphocyte syndrome and the regulation of MHC expression. Annu.
Rev. Immunol. 19:331–73
35. Meylan E, Tschopp J. 2008. NLRX1: friend or foe? EMBO Rep. 9:243–45
36. Moore CB, Bergstralh DT, Duncan JA, Lei Y, Morrison TE, et al. 2008. NLRX1 is a regulator of
mitochondrial antiviral immunity. Nature 451:573–77
37. Tattoli I, Carneiro LA, Jéhanno M, Magalhaes JG, Shu Y, et al. 2008. NLRX1 is a mitochondrial NOD-
like receptor that amplifies NF-κB and JNK pathways by inducing reactive oxygen species production.
EMBO Rep. 9:293–300
38. Vinzing M, Eitel J, Lippmann J, Hocke AC, Zahlten J, et al. 2008. NAIP and Ipaf control Legionella
pneumophila replication in human cells. J. Immunol. 180:6808–15
39. Kummer JA, Broekhuizen R, Everett H, Agostini L, Kuijk L, et al. 2007. Inflammasome components
NALP 1 and 3 show distinct but separate expression profiles in human tissues suggesting a site-specific
role in the inflammatory response. J. Histochem. Cytochem. 55:443–52
40. McCall SH, Sahraei M, Young AB, Worley CS, Duncan JA, et al. 2008. Osteoblasts express NLRP3, a
nucleotide-binding domain and leucine-rich repeat region containing receptor implicated in bacterially
induced cell death. J. Bone Miner. Res. 23:30–40
41. Poyet JL, Srinivasula SM, Tnani M, Razmara M, Fernandes-Alnemri T, Alnemri ES. 2001. Identification
of Ipaf, a human caspase-1-activating protein related to Apaf-1. J. Biol. Chem. 276:28309–13

256 Martinon · Mayor · Tschopp

 ANRV371-IY27-09 ARI 16 February 2009 8:57

42. Diez E, Yaraghi Z, MacKenzie A, Gros P. 2000. The neuronal apoptosis inhibitory protein (Naip) is
expressed in macrophages and is modulated after phagocytosis and during intracellular infection with
Legionella pneumophila. J. Immunol. 164:1470–77
43. McDaniel P, Wu X. 2008. Identification of oocyte-selective NLRP genes in rhesus macaque monkeys
(Macaca mulatta). Mol. Reprod. Dev. 76:151–59
44. Becker CE, O’Neill LA. 2007. Inflammasomes in inflammatory disorders: the role of TLRs and their
interactions with NLRs. Semin. Immunopathol. 29:239–48
45. Caplan J, Padmanabhan M, Dinesh-Kumar SP. 2008. Plant NB-LRR immune receptors: from recogni-
tion to transcriptional reprogramming. Cell Host Microbe 3:126–35
46. Tan X, Meyers BC, Kozik A, West MA, Morgante M, et al. 2007. Global expression analysis of nucleotide
binding site-leucine rich repeat-encoding and related genes in Arabidopsis. BMC Plant Biol. 7:56
47. Bent AF, Mackey D. 2007. Elicitors, effectors, and R genes: the new paradigm and a lifetime supply of
questions. Annu. Rev. Phytopathol. 45:399–436
48. Ausubel F. 2005. Are innate immune signaling pathways in plants and animals conserved? Nat. Immunol.
Annu. Rev. Immunol. 2009.27:229-265. Downloaded from arjournals.annualreviews.org

6:973–79
by Universidad Nacional Autonoma de Mexico on 03/24/09. For personal use only.

49. Staal J, Dixelius C. 2007. Tracing the ancient origins of plant innate immunity. Trends Plant Sci. 12:334–42
50. Tauber AI. 1992. The birth of immunology. III. The fate of the phagocytosis theory. Cell Immunol.
139:505–30
51. Hibino T, Loza-Coll M, Messier C, Majeske AJ, Cohen AH, et al. 2006. The immune gene repertoire
encoded in the purple sea urchin genome. Dev. Biol. 300:349–65
52. Rast JP, Smith LC, Loza-Coll M, Hibino T, Litman GW. 2006. Genomic insights into the immune
system of the sea urchin. Science 314:952–56
53. Laing K, Purcell M, Winton J, Hansen J. 2008. A genomic view of the NOD-like receptor family in
teleost fish: identification of a novel NLR subfamily in zebrafish. BMC Evol. Biol. 8:42
54. Stein C, Caccamo M, Laird G, Leptin M. 2007. Conservation and divergence of gene families encoding
components of innate immune response systems in zebrafish. Genome Biol. 8:R251
55. Chae JJ, Wood G, Masters SL, Richard K, Park G, et al. 2006. The B30.2 domain of pyrin, the familial
Mediterranean fever protein, interacts directly with caspase-1 to modulate IL-1β production. Proc. Natl.
Acad. Sci. USA 103:9982–87
56. Papin S, Cuenin S, Agostini L, Martinon F, Werner S, et al. 2007. The SPRY domain of Pyrin, mutated in
familial Mediterranean fever patients, interacts with inflammasome components and inhibits proIL-1β
processing. Cell Death Differ. 14:1457–66
57. Lespinet O, Wolf YI, Koonin EV, Aravind L. 2002. The role of lineage-specific gene family expansion
in the evolution of Eukaryotes. Genome Res. 12:1048–59
58. Bertin J, Nir WJ, Fischer CM, Tayber OV, Errada PR, et al. 1999. Human CARD4 protein is a novel
CED-4/Apaf-1 cell death family member that activates NF-κB. J. Biol. Chem. 274:12955–58
59. Inohara N, Koseki T, del Peso L, Hu Y, Yee C, et al. 1999. Nod1, an Apaf-1-like activator of caspase-9
and nuclear factor-κB. J. Biol. Chem. 274:14560–67
60. Tattoli I, Travassos L, Carneiro LA, Magalhaes J, Girardin S. 2007. The Nodosome: Nod1 and Nod2
control bacterial infections and inflammation. Semin. Immunopathol. 29:289–301
61. Hsu Y, Zhang Y, You Y, Wang D, Li H, et al. 2007. The adaptor protein CARD9 is required for innate
immune responses to intracellular pathogens. Nat. Immunol. 8:198–205
62. Mcdonald C, Inohara N, Nunez G. 2005. Peptidoglycan signaling in innate immunity and inflammatory
disease. J. Biol. Chem. 280:20177–80
63. Girardin SE, Philpott DJ. 2004. Mini-review: the role of peptidoglycan recognition in innate immunity.
Eur. J. Immunol. 34:1777–82
64. Viala J, Chaput C, Boneca I, Cardona A, Girardin SE, et al. 2004. Nod1 responds to peptidoglycan
delivered by the Helicobacter pylori cag pathogenicity island. Nat. Immunol. 5:1166–74
65. Kobayashi KS, Chamaillard M, Ogura Y, Henegariu O, Inohara N, et al. 2005. Nod2-dependent regu-
lation of innate and adaptive immunity in the intestinal tract. Science 307:731–34
66. Vignal C, Singer E, Peyrin-Biroulet L, Desreumaux P, Chamaillard M. 2007. How NOD2 mutations
predispose to Crohn’s disease? Microbes Infect. 9:658–63

www.annualreviews.org • The Inflammasomes 257

 ANRV371-IY27-09 ARI 16 February 2009 8:57

67. Tanabe T, Chamaillard M, Ogura Y, Zhu L, Qiu S, et al. 2004. Regulatory regions and critical residues
of NOD2 involved in muramyl dipeptide recognition. EMBO J. 23:1587–97
68. Hsu LC, Ali SR, McGillivray S, Tseng PH, Mariathasan S, et al. 2008. A NOD2-NALP1 complex
mediates caspase-1-dependent IL-1β secretion in response to Bacillus anthracis infection and muramyl
dipeptide. Proc. Natl. Acad. Sci. USA 105:7803–8
69. Pan Q, Mathison J, Fearns C, Kravchenko VV, Da Silva Correia J, et al. 2007. MDP-induced interleukin-
1β processing requires Nod2 and CIAS1/NALP3. J. Leukoc. Biol. 82:177–83
70. Describes the 70. Martinon F, Burns K, Tschopp J. 2002. The inflammasome: a molecular platform triggering
inflammasome for the activation of inflammatory caspases and processing of proIL-1β. Mol. Cell 10:417–26
first time. 71. Zou H, Li Y, Liu X, Wang X. 1999. An APAF-1.cytochrome c multimeric complex is a functional
apoptosome that activates procaspase-9. J. Biol. Chem. 274:11549–56
72. Cohen GM. 1997. Caspases: the executioners of apoptosis. Biochem. J. 326(Pt. 1):1–16
73. Fuentes-Prior P, Salvesen GS. 2004. The protein structures that shape caspase activity, specificity, acti-
vation and inhibition. Biochem. J. 384:201–32
Annu. Rev. Immunol. 2009.27:229-265. Downloaded from arjournals.annualreviews.org

74. Boatright KM, Salvesen GS. 2003. Mechanisms of caspase activation. Curr. Opin. Cell Biol. 15:725–31
by Universidad Nacional Autonoma de Mexico on 03/24/09. For personal use only.

75. Nadiri A, Wolinski MK, Saleh M. 2006. The inflammatory caspases: key players in the host response to
pathogenic invasion and sepsis. J. Immunol. 177:4239–45
77. Identifies ASC and 76. Martinon F, Gaide O, Pétrilli V, Mayor A, Tschopp J. 2007. NALP inflammasomes: a central role in
IPAF as essential innate immunity. Semin. Immunopathol. 29:213–29
inflammasome 77. Mariathasan S, Newton K, Monack DM, Vucic D, French DM, et al. 2004. Differential activation
components in mice. of the inflammasome by caspase-1 adaptors ASC and Ipaf. Nature 430:213–18
78. Agostini L, Burns K, McDermott MF, Hawkins PN, Tschopp J. 2004. NALP3 forms an IL-1β-
processing inflammasome with increased activity in Muckle-Wells autoinflammatory disorder.
78. Describes the Immunity 20:319–25
NALP3 inflammasome 79. Duncan JA, Bergstralh DT, Wang Y, Willingham SB, Ye Z, et al. 2007. Cryopyrin/NALP3 binds
and its overactivation in ATP/dATP, is an ATPase, and requires ATP binding to mediate inflammatory signaling. Proc. Natl.
MWS patients for the Acad. Sci. USA 104:8041–46
first time. 80. Lu C, Wang A, Wang L, Dorsch M, Ocain TD, Xu Y. 2005. Nucleotide binding to CARD12 and its
role in CARD12-mediated caspase-1 activation. Biochem. Biophys. Res. Commun. 331:1114–19
81. Mayor A, Martinon F, De Smedt T, Pétrilli V, Tschopp J. 2007. A crucial function of SGT1 and HSP90
in inflammasome activity links mammalian and plant innate immune responses. Nat. Immunol. 8:497–503
82. Da Silva Correia J, Miranda Y, Leonard N, Ulevitch R. 2007. SGT1 is essential for Nod1 activation.
Proc. Natl. Acad. Sci. USA 104:6764–69
83. Chapelsky S, Batty S, Frost M, Mogridge J. 2008. Inhibition of anthrax lethal toxin-induced cytolysis of
RAW264.7 cells by celastrol. PLoS ONE 3:e1421
84. Miao EA, Andersen-Nissen E, Warren SE, Aderem A. 2007. TLR5 and Ipaf: dual sensors of bacterial
flagellin in the innate immune system. Semin. Immunopathol. 29:275–88
85. Franchi L, Park JH, Shaw MH, Marina-Garcia N, Chen G, et al. 2008. Intracellular NOD-like receptors
in innate immunity, infection and disease. Cell Microbiol. 10:1–8
86. Martinon F. 2007. Orchestration of pathogen recognition by inflammasome diversity: variations on a
common theme. Eur. J. Immunol. 37:3003–6
87. Matzinger P. 1994. Tolerance, danger, and the extended family. Annu. Rev. Immunol. 12:991–1045
88. Rock KL, Kono H. 2008. The inflammatory response to cell death. Annu. Rev. Pathol. 3:99–126
89. Kono H, Rock KL. 2008. How dying cells alert the immune system to danger. Nat. Rev. Immunol.
8:279–89
90. Rock KL, Hearn A, Chen CJ, Shi Y. 2005. Natural endogenous adjuvants. Springer Semin. Immunopathol.
26:231–46
91. Schneider DS. 2002. Plant immunity and film noir: what gumshoe detectives can teach us about plant-
pathogen interactions. Cell 109:537–40
92. Kostura MJ, Tocci MJ, Limjuco G, Chin J, Cameron P, et al. 1989. Identification of a monocyte specific
preinterleukin 1 β convertase activity. Proc. Natl. Acad. Sci. USA 86:5227–31
93. Pétrilli V, Papin S, Dostert C, Mayor A, Tschopp J. 2007. Activation of the NALP3 inflammasome is
triggered by low intracellular potassium concentration. Cell Death Differ. 14:1583–89

258 Martinon · Mayor · Tschopp

 ANRV371-IY27-09 ARI 16 February 2009 8:57

94. Kahlenberg JM, Dubyak GR. 2004. Mechanisms of caspase-1 activation by P2X7 receptor-mediated K+
release. Am. J. Physiol. Cell Physiol. 286:C1100–8
95. Franchi L, Kanneganti T, Dubyak GR, Núñez G. 2007. Differential requirement of P2X7 receptor and
intracellular K+ for caspase-1 activation induced by intracellular and extracellular bacteria. J. Biol. Chem.
282:18810–18
96. Mariathasan S, Weiss DS, Newton K, McBride J, O’Rourke K, et al. 2006. Cryopyrin activates the
inflammasome in response to toxins and ATP. Nature 440:228–32
97. Sutterwala FS, Ogura Y, Szczepanik M, Lara-Tejero M, Lichtenberger GS, et al. 2006. Critical 97. Demonstrates for
role for NALP3/CIAS1/cryopyrin in innate and adaptive immunity through its regulation of the first time that the
caspase-1. Immunity 24:317–27 NALP3 inflammasome
98. Kanneganti TD, Ozören N, Body-Malapel M, Amer A, Park JH, et al. 2006. Bacterial RNA and small is implicated in Type IV
hypersensitivity.
antiviral compounds activate caspase-1 through cryopyrin/Nalp3. Nature 440:233–36
99. Haag F, Adriouch S, Braß A, Jung C, Möller S, et al. 2007. Extracellular NAD and ATP: partners in
immune cell modulation. Purinergic Signal 3:71–81
Annu. Rev. Immunol. 2009.27:229-265. Downloaded from arjournals.annualreviews.org

100. Eckle T, Füllbier L, Wehrmann M, Khoury J, Mittelbronn M, et al. 2007. Identification of ectonucleo-
by Universidad Nacional Autonoma de Mexico on 03/24/09. For personal use only.

tidases CD39 and CD73 in innate protection during acute lung injury. J. Immunol. 178:8127–37
101. Communi D, Janssens R, Suarez-Huerta N, Robaye B, Boeynaems JM. 2000. Advances in signalling by
extracellular nucleotides: the role and transduction mechanisms of P2Y receptors. Cell Signal. 12:351–60
102. Novak I. 2003. ATP as a signaling molecule: the exocrine focus. News Physiol. Sci. 18:12–17
103. MacDonald PE, Braun M, Galvanovskis J, Rorsman P. 2006. Release of small transmitters through
kiss-and-run fusion pores in rat pancreatic beta cells. Cell Metab. 4:283–90
104. Koshlukova SE, Lloyd TL, Araujo MW, Edgerton M. 1999. Salivary histatin 5 induces nonlytic release
of ATP from Candida albicans leading to cell death. J. Biol. Chem. 274:18872–79
105. Laliberte RE, Eggler J, Gabel CA. 1999. ATP treatment of human monocytes promotes caspase-1
maturation and externalization. J. Biol. Chem. 274:36944–51
106. Kanneganti TD, Lamkanfi M, Kim YG, Chen G, Park JH, et al. 2007. Pannexin-1-mediated recognition
of bacterial molecules activates the cryopyrin inflammasome independent of Toll-like receptor signaling.
Immunity 26:433–43
107. Locovei S, Bao L, Dahl GP. 2006. Pannexin 1 in erythrocytes: function without a gap. Proc. Natl. Acad.
Sci. USA 103:7655–59
108. Piccini A, Carta S, Tassi S, Lasiglié D, Fossati G, Rubartelli A. 2008. ATP is released by monocytes
stimulated with pathogen-sensing receptor ligands and induces IL-1β and IL-18 secretion in an autocrine
way. Proc. Natl. Acad. Sci. USA 105:8067–72
109. Yamamoto M, Yaginuma K, Tsutsui H, Sagara J, Guan X, et al. 2004. ASC is essential for LPS-induced
activation of procaspase-1 independently of TLR-associated signal adaptor molecules. Genes Cells 9:1055–
67
110. Idzko M, Hammad H, van Nimwegen M, Kool M, Willart MA, et al. 2007. Extracellular ATP triggers
and maintains asthmatic airway inflammation by activating dendritic cells. Nat. Med. 13:913–19
111. Shi Y, Evans JE, Rock KL. 2003. Molecular identification of a danger signal that alerts the immune 111. Identifies uric acid
system to dying cells. Nature 425:516–21 as an endogenous
112. Chen CJ, Shi Y, Hearn A, Fitzgerald K, Golenbock D, et al. 2006. MyD88-dependent IL-1 receptor adjuvant released by
signaling is essential for gouty inflammation stimulated by monosodium urate crystals. J. Clin. Invest. damaged cells.
116:2262–71
113. Eisenbarth SC, Colegio OR, O’Connor W, Sutterwala FS, Flavell RA. 2008. Crucial role for
the Nalp3 inflammasome in the immunostimulatory properties of aluminium adjuvants. Nature 113. Describes, as do
453:1122–26 117, 118, 119, and 129,
114. Shi Y, Galusha SA, Rock KL. 2006. Cutting edge: elimination of an endogenous adjuvant reduces the the activation of the
NALP3 inflammasome
activation of CD8 T lymphocytes to transplanted cells and in an autoimmune diabetes model. J. Immunol.
by alum adjuvants.
176:3905–8
115. Orengo J, Evans J, Bettiol E, Leliwa-Sytek A, Day K, et al. 2008. Plasmodium-induced inflammation by
uric acid. PLoS Pathogens 4:e1000013
116. Kool M, Soullié T, Van Nimwegen M, Willart MA, Muskens F, et al. 2008. Alum adjuvant boosts adaptive
immunity by inducing uric acid and activating inflammatory dendritic cells. J. Exp. Med. 205:869–82

www.annualreviews.org • The Inflammasomes 259

 ANRV371-IY27-09 ARI 16 February 2009 8:57

117. Li H, Willingham SB, Ting JP, Re F. 2008. Cutting edge: inflammasome activation by alum and alum’s
adjuvant effect are mediated by NLRP3. J. Immunol. 181:17–21
118. Franchi L, Núñez G. 2008. The Nlrp3 inflammasome is critical for aluminium hydroxide-mediated
IL-1β secretion but dispensable for adjuvant activity. Eur. J. Immunol. 38:2085–89
119. Kool M, Pétrilli V, De Smedt T, Rolaz A, Hammad H, et al. 2008. Alum adjuvant stimulates inflammatory
dendritic cells through activation of the NALP3 inflammasome. J. Immunol. 205:869–82
120. Kutzing MK, Firestein BL. 2008. Altered uric acid levels and disease states. J. Pharmacol. Exp. Ther.
324:1–7
121. Lioté F, Ea HK. 2007. Recent developments in crystal-induced inflammation pathogenesis and man-
agement. Curr. Rheumatol. Rep. 9:243–50
122. So A, De Smedt T, Revaz S, Tschopp J. 2007. A pilot study of IL-1 inhibition by anakinra in acute gout.
Arthritis Res. Ther. 9:R28
123. McGonagle D, Tan A, Shankaranarayana S, Madden J, Emery P, McDermott M. 2007. Management of
treatment resistant inflammation of acute or chronic tophaceous gout with anakinra. Ann. Rheum. Dis.
Annu. Rev. Immunol. 2009.27:229-265. Downloaded from arjournals.annualreviews.org

66:1683–84
by Universidad Nacional Autonoma de Mexico on 03/24/09. For personal use only.

124. McGonagle D, Tan AL, Madden J, Emery P, McDermott MF. 2008. Successful treatment of resistant
pseudogout with anakinra. Arthritis Rheum. 58:631–33
125. Otsuki T, Maeda M, Murakami S, Hayashi H, Miura Y, et al. 2007. Immunological effects of silica and
asbestos. Cell Mol. Immunol. 4:261–68
126. Wagner GR. 1997. Asbestosis and silicosis. Lancet 349:1311–15
127. Dostert C, Petrilli V, van Bruggen R, Steele C, Mossman BT, Tschopp J. 2008. Innate immune activation
through Nalp3 inflammasome sensing of asbestos and silica. Science 320:674–77
128. Cassel SL, Eisenbarth SC, Iyer SS, Sadler JJ, Colegio OR, et al. 2008. The Nalp3 inflammasome is
essential for the development of silicosis. Proc. Natl. Acad. Sci. USA 105:9035–40
129. Hornung V, Bauernfeind F, Halle A, Samstad EO, Kono H, et al. 2008. Silica crystals and aluminum
salts activate the NALP3 inflammasome through phagosomal destabilization. Nat. Immunol. 9:847–56
130. McKee AS, Munks MW, Marrack P. 2007. How do adjuvants work? Important considerations for new
generation adjuvants. Immunity 27:687–90
131. Lindblad EB. 2004. Aluminium compounds for use in vaccines. Immunol. Cell Biol. 82:497–505
132. Mannhalter JW, Neychev HO, Zlabinger GJ, Ahmad R, Eibl MM. 1985. Modulation of the human
immune response by the nontoxic and nonpyrogenic adjuvant aluminium hydroxide: effect on antigen
uptake and antigen presentation. Clin. Exp. Immunol. 61:143–51
133. Grun JL, Maurer PH. 1989. Different T helper cell subsets elicited in mice utilizing two different adjuvant
vehicles: the role of endogenous interleukin 1 in proliferative responses. Cell Immunol. 121:134–45
134. Li H, Nookala S, Re F. 2007. Aluminum hydroxide adjuvants activate caspase-1 and induce IL-1β and
IL-18 release. J. Immunol. 178:5271–76
135. Feldmeyer L, Keller M, Niklaus G, Hohl D, Werner S, Beer HD. 2007. The inflammasome mediates
UVB-induced activation and secretion of interleukin-1β by keratinocytes. Curr. Biol. 17:1140–45
136. Cavani A, De Pità O, Girolomoni G. 2007. New aspects of the molecular basis of contact allergy. Curr.
Opin. Allergy Clin. Immunol. 7:404–8
137. Shornick LP, De Togni P, Mariathasan S, Goellner J, Strauss-Schoenberger J, et al. 1996. Mice deficient
in IL-1β manifest impaired contact hypersensitivity to trinitrochlorobenzone. J. Exp. Med. 183:1427–36
138. Zepter K, Häffner A, Soohoo LF, De Luca D, Tang HP, et al. 1997. Induction of biologically active
IL-1β-converting enzyme and mature IL-1β in human keratinocytes by inflammatory and immunologic
stimuli. J. Immunol. 159:6203–8
139. Antonopoulos C, Cumberbatch M, Dearman RJ, Daniel RJ, Kimber I, Groves RW. 2001. Functional
caspase-1 is required for Langerhans cell migration and optimal contact sensitization in mice. J. Immunol.
166:3672–77
140. Wang B, Feliciani C, Howell BG, Freed I, Cai Q, et al. 2002. Contribution of Langerhans cell-derived
IL-18 to contact hypersensitivity. J. Immunol. 168:3303–8
141. Watanabe H, Gaide O, Pétrilli V, Martinon F, Contassot E, et al. 2007. Activation of the IL-1β-
processing inflammasome is involved in contact hypersensitivity. J. Invest. Dermatol. 127:1956–63

260 Martinon · Mayor · Tschopp

 ANRV371-IY27-09 ARI 16 February 2009 8:57

142. Yazdi AS, Ghoreschi K, Röcken M. 2007. Inflammasome activation in delayed-type hypersensitivity
reactions. J. Investig. Dermatol. 127:1853–55
143. Watanabe H, Gehrke S, Contassot E, Roques S, Tschopp J, et al. 2008. Danger signaling through the
inflammasome acts as a master switch between tolerance and sensitization. J. Immunol. 180:5826–32
144. Cannon GJ, Swanson JA. 1992. The macrophage capacity for phagocytosis. J. Cell Sci. 101(Pt. 4):907–13
145. Khandani A, Eng E, Jongstra-Bilen J, Schreiber AD, Douda D, et al. 2007. Microtubules regulate PI-3K
activity and recruitment to the phagocytic cup during Fcγ receptor-mediated phagocytosis in nonelicited
macrophages. J. Leukoc. Biol. 82:417–28
146. Nuki G, Simkin PA. 2006. A concise history of gout and hyperuricemia and their treatment. Arthritis
Res. Ther. 8(Suppl. 1):S1
147. Fubini B, Hubbard A. 2003. Reactive oxygen species (ROS) and reactive nitrogen species (RNS) gener-
ation by silica in inflammation and fibrosis. Free Radic. Biol. Med. 34:1507–16
148. Simeonova PP, Luster MI. 1995. Iron and reactive oxygen species in the asbestos-induced tumor necrosis
factor-α response from alveolar macrophages. Am. J. Respir. Cell Mol. Biol. 12:676–83
Annu. Rev. Immunol. 2009.27:229-265. Downloaded from arjournals.annualreviews.org

149. Cruz CM, Rinna A, Forman HJ, Ventura AL, Persechini PM, Ojcius DM. 2007. ATP activates a reac-
by Universidad Nacional Autonoma de Mexico on 03/24/09. For personal use only.

tive oxygen species-dependent oxidative stress response and secretion of proinflammatory cytokines in
macrophages. J. Biol. Chem. 282:2871–79
150. Bossi O, Gartsbein M, Leitges M, Kuroki T, Grossman S, Tennenbaum T. 2008. UV irradiation increases
ROS production via PKCδ signaling in primary murine fibroblasts. J. Cell Biochem. 105:194–207.
151. Rutault K, Alderman C, Chain BM, Katz DR. 1999. Reactive oxygen species activate human peripheral
blood dendritic cells. Free Radic. Biol. Med. 26:232–38
152. Bolwell GP. 1999. Role of active oxygen species and NO in plant defence responses. Curr. Opin. Plant
Biol. 2:287–94
153. Fay AJ, Qian X, Jan YN, Jan LY. 2006. SK channels mediate NADPH oxidase-independent reactive
oxygen species production and apoptosis in granulocytes. Proc. Natl. Acad. Sci. USA 103:17548–53
154. Ishii KJ, Koyama S, Nakagawa A, Coban C, Akira S. 2008. Host innate immune receptors and beyond:
making sense of microbial infections. Cell Host Microbe 3:352–63
155. Freche B, Reig N, Van Der Goot FG. 2007. The role of the inflammasome in cellular responses to toxins
and bacterial effectors. Semin. Immunopathol. 29:249–60
156. Brown N, Wickham M, Coombes B, Finlay BB. 2006. Crossing the line: selection and evolution of
virulence traits. PLoS Pathog. 2:e42
157. Strominger JL. 2007. Bacterial cell walls, innate immunity and immunoadjuvants. Nat. Immunol. 8:1269–
71
158. Oppenheim JJ, Togawa A, Chedid L, Mizel S. 1980. Components of mycobacteria and muramyl dipeptide
with adjuvant activity induce lymphocyte activating factor. Cell Immunol. 50:71–81
159. Martinon F, Agostini L, Meylan E, Tschopp J. 2004. Identification of bacterial muramyl dipeptide as
activator of the NALP3/cryopyrin inflammasome. Curr. Biol. 14:1929–34
160. Marina-Garcia N, Franchi L, Kim Y, Miller D, Mcdonald C, et al. 2008. Pannexin-1-mediated intracel-
lular delivery of muramyl dipeptide induces caspase-1 activation via cryopyrin/NLRP3 independently
of Nod2. J. Immunol. 180:4050–57
161. Nagao S, Akagawa KS, Yamada K, Yagawa K, Tokunaga T, Kotani S. 1990. Lack of response of murine
peritoneal macrophages to in vitro activation by muramyl dipeptide (MDP). I. Macrophage activation
by MDP is species dependent. Microbiol. Immunol. 34:323–35
162. Staruch MJ, Wood DD. 1982. Genetic influences on the adjuvanticity of muramyl dipeptide in vivo.
J. Immunol. 128:155–60
163. Ferwerda G, Kramer M, de Jong D, Piccini A, Joosten LA, et al. 2008. Engagement of NOD2 has a dual
effect on proIL-1β mRNA transcription and secretion of bioactive IL-1β. Eur. J. Immunol. 38:184–91
164. Maeda S, Hsu LC, Liu H, Bankston LA, Iimura M, et al. 2005. Nod2 mutation in Crohn’s disease
potentiates NF-κB activity and IL-1β processing. Science 307:734–38
165. Bruey JM, Bruey-Sedano N, Luciano F, Zhai D, Balpai R, et al. 2007. Bcl-2 and Bcl-XL regulate
proinflammatory caspase-1 activation by interaction with NALP1. Cell 129:45–56
166. Takaoka A, Wang Z, Choi MK, Yanai H, Negishi H, et al. 2007. DAI (DLM-1/ZBP1) is a cytosolic
DNA sensor and an activator of innate immune response. Nature 448:501–5

www.annualreviews.org • The Inflammasomes 261

 ANRV371-IY27-09 ARI 16 February 2009 8:57

167. Kumagai Y, Takeuchi O, Akira S. 2008. TLR9 as a key receptor for the recognition of DNA. Adv. Drug
Deliv. Rev. 60:795–804
168. Muruve DA, Pétrilli V, Zaiss AK, White LR, Clark SA, et al. 2008. The inflammasome recognizes
cytosolic microbial and host DNA and triggers an innate immune response. Nature 452:103–7
169. Kanneganti TD, Body-Malapel M, Amer A, Park JH, Whitfield J, et al. 2006. Critical role for
Cryopyrin/Nalp3 in activation of caspase-1 in response to viral infection and double-stranded RNA.
J. Biol. Chem. 281:36560–68
170. Gonzalez MR, Bischofberger M, Pernot L, Van Der Goot FG, Frêche B. 2008. Bacterial pore-forming
toxins: the (w)hole story? Cell Mol. Life Sci. 65:493–507
171. Gurcel L, Abrami L, Girardin S, Tschopp J, Van Der Goot FG. 2006. Caspase-1 activation of lipid
metabolic pathways in response to bacterial pore-forming toxins promotes cell survival. Cell 126:1135–
45
172. Ozören N, Masumoto J, Franchi L, Kanneganti TD, Body-Malapel M, et al. 2006. Distinct roles of
TLR2 and the adaptor ASC in IL-1β/IL-18 secretion in response to Listeria monocytogenes. J. Immunol.
Annu. Rev. Immunol. 2009.27:229-265. Downloaded from arjournals.annualreviews.org

176:4337–42
by Universidad Nacional Autonoma de Mexico on 03/24/09. For personal use only.

173. Hara H, Tsuchiya K, Nomura T, Kawamura I, Shoma S, Mitsuyama M. 2008. Dependency of caspase-1
activation induced in macrophages by Listeria monocytogenes on cytolysin, listeriolysin O, after evasion
from phagosome into the cytoplasm. J. Immunol. 180:7859–68
174. Warren SE, Mao DP, Rodriguez AE, Miao EA, Aderem A. 2008. Multiple Nod-like receptors activate
caspase 1 during Listeria monocytogenes infection. J. Immunol. 180:7558–64
175. Boyden E, Dietrich W. 2006. Nalp1b controls mouse macrophage susceptibility to anthrax lethal toxin.
Nat. Genet. 38:240–44
176. Fink SL, Bergsbaken T, Cookson BT. 2008. Anthrax lethal toxin and Salmonella elicit the common cell
death pathway of caspase-1-dependent pyroptosis via distinct mechanisms. Proc. Natl. Acad. Sci. USA
105:4312–17
177. Wickliffe KE, Leppla SH, Moayeri M. 2008. Anthrax lethal toxin-induced inflammasome formation and
caspase-1 activation are late events dependent on ion fluxes and the proteasome. Cell Microbiol. 10:332–43
178. Squires RC, Muehlbauer SM, Brojatsch J. 2007. Proteasomes control caspase-1 activation in anthrax
lethal toxin-mediated cell killing. J. Biol. Chem. 282:34260–67
179. Lara-Tejero M, Sutterwala FS, Ogura Y, Grant EP, Bertin J, et al. 2006. Role of the caspase-1 inflam-
masome in Salmonella typhimurium pathogenesis. J. Exp. Med. 203:1407–12
180. Molofsky AB, Byrne BG, Whitfield NN, Madigan CA, Fuse ET, et al. 2006. Cytosolic recognition of
flagellin by mouse macrophages restricts Legionella pneumophila infection. J. Exp. Med. 203:1093–104
181. Ren T, Zamboni DS, Roy CR, Dietrich W, Vance RE. 2006. Flagellin-deficient Legionella mutants
evade caspase-1- and Naip5-mediated macrophage immunity. PLoS Pathog. 2:e18
182. Zamboni DS, Kobayashi KS, Kohlsdorf T, Ogura Y, Long EM, et al. 2006. The Birc1e cytosolic pattern-
recognition receptor contributes to the detection and control of Legionella pneumophila infection. Nat.
Immunol. 7:318–25
183. Lamkanfi M, Amer A, Kanneganti TD, Muñoz-Planillo R, Chen G, et al. 2007. The Nod-like receptor
family member Naip5/Birc1e restricts Legionella pneumophila growth independently of caspase-1 activa-
tion. J. Immunol. 178:8022–27
184. Pedra JH, Sutterwala FS, Sukumaran B, Ogura Y, Qian F, et al. 2007. ASC/PYCARD and caspase-1
regulate the IL-18/IFN-γ axis during Anaplasma phagocytophilum infection. J. Immunol. 179:4783–91
185. Miao EA, Ernst RK, Dors M, Mao DP, Aderem A. 2008. Pseudomonas aeruginosa activates caspase 1
through Ipaf. Proc. Natl. Acad. Sci. USA 105:2562–67
186. Sutterwala FS, Mijares LA, Li L, Ogura Y, Kazmierczak BI, Flavell RA. 2007. Immune recognition of
Pseudomonas aeruginosa mediated by the IPAF/NLRC4 inflammasome. J. Exp. Med. 204:3235–45
187. Franchi L, Stoolman J, Kanneganti TD, Verma A, Ramphal R, Núñez G. 2007. Critical role for Ipaf in
Pseudomonas aeruginosa-induced caspase-1 activation. Eur. J. Immunol. 37:3030–39
188. Suzuki T, Franchi L, Toma C, Ashida H, Ogawa M, et al. 2007. Differential regulation of caspase-1
activation, pyroptosis, and autophagy via Ipaf and ASC in Shigella-infected macrophages. PLoS Pathog.
3:e111

262 Martinon · Mayor · Tschopp

 ANRV371-IY27-09 ARI 16 February 2009 8:57

189. Henry T, Brotcke A, Weiss DS, Thompson LJ, Monack DM. 2007. Type I interferon signaling is required
for activation of the inflammasome during Francisella infection. J. Exp. Med. 204:987–94
190. Greten FR, Arkan MC, Bollrath J, Hsu LC, Goode J, et al. 2007. NF-κB is a negative regulator of IL-1β
secretion as revealed by genetic and pharmacological inhibition of IKKβ. Cell 130:918–31
191. Stehlik C, Dorfleutner A. 2007. COPs and POPs: Modulators of inflammasome activity. J. Immunol.
179:7993–98
192. Dorfleutner A, Talbott SJ, Bryan NB, Funya KN, Rellick SL, et al. 2007. A Shope Fibroma virus PYRIN-
only protein modulates the host immune response. Virus Genes 35:685–94
193. Benedict CA, Ware CF. 2005. Poxviruses aren’t stuPYD. Immunity 23:553–55
194. Johnston JB, Barrett JW, Nazarian SH, Goodwin M, Ricciuto D, et al. 2005. A poxvirus-encoded pyrin
domain protein interacts with ASC-1 to inhibit host inflammatory and apoptotic responses to infection.
Immunity 23:587–98
195. Bedoya F, Sandler LL, Harton JA. 2007. Pyrin-only protein 2 modulates NF-κB and disrupts ASC:CLR
interactions. J. Immunol. 178:3837–45
Annu. Rev. Immunol. 2009.27:229-265. Downloaded from arjournals.annualreviews.org

196. The French FMF Consortium. 1997. A candidate gene for familial Mediterranean fever. Nat. Genet.
by Universidad Nacional Autonoma de Mexico on 03/24/09. For personal use only.

17:25–31
197. Chae JJ, Komarow HD, Cheng J, Wood G, Raben N, et al. 2003. Targeted disruption of pyrin, the
FMF protein, causes heightened sensitivity to endotoxin and a defect in macrophage apoptosis. Mol. Cell
11:591–604
198. Fernandes-Alnemri T, Wu J, Yu JW, Datta P, Miller B, et al. 2007. The pyroptosome: a supramolecular
assembly of ASC dimers mediating inflammatory cell death via caspase-1 activation. Cell Death Differ.
14:1590–604
199. McDermott MF. 2004. A common pathway in periodic fever syndromes. Trends Immunol. 25:457–60
200. Shoham NG, Centola M, Mansfield E, Hull KM, Wood G, et al. 2003. Pyrin binds the PSTPIP1/
CD2BP1 protein, defining familial Mediterranean fever and PAPA syndrome as disorders in the same
pathway. Proc. Natl. Acad. Sci. USA 100:13501–6
201. Grosse J, Chitu V, Marquardt A, Hanke P, Schmittwolf C, et al. 2006. Mutation of mouse Mayp/Pstpip2
causes a macrophage autoinflammatory disease. Blood 107:3350–58
202. Ferguson PJ, Bing X, Vasef MA, Ochoa LA, Mahgoub A, et al. 2006. A missense mutation in pstpip2 is
associated with the murine autoinflammatory disorder chronic multifocal osteomyelitis. Bone 38:41–47
203. da Cunha JP, Galante PA, de Souza SJ. 2008. Different evolutionary strategies for the origin of caspase-1
inhibitors. J. Mol. Evol. 66:591–97
204. Kersse K, Vanden Berghe T, Lamkanfi M, Vandenabeele P. 2007. A phylogenetic and functional overview
of inflammatory caspases and caspase-1-related CARD-only proteins. Biochem. Soc. Trans. 35:1508–11
205. Saleh M, Vaillancourt JP, Graham RK, Huyck M, Srinivasula SM, et al. 2004. Differential mod- 205. Demonstrates, as
ulation of endotoxin responsiveness by human caspase-12 polymorphisms. Nature 429:75–79 does 209, the role of
206. Kachapati K, O’Brien TR, Bergeron J, Zhang M, Dean M. 2006. Population distribution of the functional caspase-12 in regulating
endotoxin
caspase-12 allele. Hum. Mutat. 27:975
responsiveness.
207. Wang X, Grus W, Zhang J. 2006. Gene losses during human origins. PLoS Biol. 4:e52
208. Xue Y, Daly A, Yngvadottir B, Liu M, Coop G, et al. 2006. Spread of an inactive form of caspase-12 in
humans is due to recent positive selection. Am. J. Hum. Genet. 78:659–70
209. Saleh M, Mathison JC, Wolinski MK, Bensinger SJ, Fitzgerald P, et al. 2006. Enhanced bacterial clear-
ance and sepsis resistance in caspase-12-deficient mice. Nature 440:1064–68
210. Roy S, Sharom JR, Houde C, Loisel TP, Vaillancourt JP, et al. 2008. Confinement of caspase-12 prote-
olytic activity to autoprocessing. Proc. Natl. Acad. Sci. USA 105:4133–38
211. Miggin SM, Pålsson-McDermott E, Dunne A, Jefferies C, Pinteaux E, et al. 2007. NF-κB activation by
the Toll-IL-1 receptor domain protein MyD88 adapter-like is regulated by caspase-1. Proc. Natl. Acad.
Sci. USA 104:3372–77
212. Keller M, Rüegg A, Werner S, Beer HD. 2008. Active caspase-1 is a regulator of unconventional protein
secretion. Cell 132:818–31
213. Chae JJ, Wood G, Richard K, Jaffe H, Colburn NT, et al. 2008. The familial Mediterranean fever protein,
pyrin, is cleaved by caspase-1 and activates NF-κB through its N-terminal fragment. Blood 112:1794–803

www.annualreviews.org • The Inflammasomes 263

 ANRV371-IY27-09 ARI 16 February 2009 8:57

214. Dinarello CA. 2004. Infection, fever, and exogenous and endogenous pyrogens: some concepts have
changed. J. Endotoxin Res. 10:201–22
215. Samad TA, Moore KA, Sapirstein A, Billet S, Allchorne A, et al. 2001. Interleukin-1β-mediated induction
of Cox-2 in the CNS contributes to inflammatory pain hypersensitivity. Nature 410:471–75
216. McGonagle D, Savic S, McDermott MF. 2007. The NLR network and the immunological disease
continuum of adaptive and innate immune-mediated inflammation against self. Semin. Immunopathol.
29:303–13
217. Discusses the 217. McGonagle D, McDermott MF. 2006. A proposed classification of the immunological diseases.
immunological disease PLoS Med. 3:e297
continuum ranging 218. Aksentijevich I, Putnam CD, Remmers EF, Mueller JL, Le J, et al. 2007. The clinical continuum of
from autoinflammatory cryopyrinopathies: novel CIAS1 mutations in North American patients and a new cryopyrin model.
diseases to autoimmune
Arthritis Rheum. 56:1273–85
diseases.
219. Shinkai K, McCalmont TH, Leslie KS. 2008. Cryopyrin-associated periodic syndromes and autoinflam-
mation. Clin. Exp. Dermatol. 33:1–9
Annu. Rev. Immunol. 2009.27:229-265. Downloaded from arjournals.annualreviews.org

220. Masters SL, Lobito AA, Chae J, Kastner DL. 2006. Recent advances in the molecular pathogenesis of
by Universidad Nacional Autonoma de Mexico on 03/24/09. For personal use only.

hereditary recurrent fevers. Curr. Opin. Allergy Clin. Immunol. 6:428–33

221. Dowds TA, Masumoto J, Zhu L, Inohara N, Núñez G. 2004. Cryopyrin-induced interleukin 1β secretion
in monocytic cells: enhanced activity of disease-associated mutants and requirement for ASC. J. Biol.
Chem. 279:21924–28
222. Goldbach-Mansky R, Dailey NJ, Canna SW, Gelabert A, Jones J, et al. 2006. Neonatal-onset multisystem
inflammatory disease responsive to interleukin-1β inhibition. N. Engl. J. Med. 355:581–92
223. Hawkins PN, Lachmann HJ, Aganna E, McDermott MF. 2004. Spectrum of clinical features in Muckle-
Wells syndrome and response to anakinra. Arthritis Rheum. 50:607–12
224. Demonstrates for 224. Hawkins PN, Lachmann HJ, McDermott MF. 2003. Interleukin-1-receptor antagonist in the
the first time the Muckle-Wells syndrome. N. Engl. J. Med. 348:2583–84
spectacular effect of 225. Hoffman HM, Rosengren S, Boyle DL, Cho JY, Nayar J, et al. 2004. Prevention of cold-associated acute
IL-1 signaling blockade inflammation in familial cold autoinflammatory syndrome by interleukin-1 receptor antagonist. Lancet
in diseases
364:1779–85
characterized by
226. McDermott MF, Tschopp J. 2007. From inflammasomes to fevers, crystals and hypertension: how basic
inflammasome
research explains inflammatory diseases. Trends Mol. Med. 13:381–88
overactivation.
227. Gavin AL, Hoebe K, Duong B, Ota T, Martin C, et al. 2006. Adjuvant-enhanced antibody responses in
the absence of Toll-like receptor signaling. Science 314:1936–38
228. Rao DA, Tracey KJ, Pober JS. 2007. IL-1α and IL-1β are endogenous mediators linking cell injury to
the adaptive alloimmune response. J. Immunol. 179:6536–46
229. Acosta-Rodriguez EV, Napolitani G, Lanzavecchia A, Sallusto F. 2007. Interleukins 1β and 6 but not
transforming growth factor-β are essential for the differentiation of interleukin 17-producing human T
helper cells. Nat. Immunol. 8:942–49
230. Chedid L. 1985. Adjuvants of immunity. Ann. Inst. Pasteur Immunol. 136D:283–91
231. Misson P, Brombacher F, Delos M, Lison D, Huaux F. 2007. Type 2 immune response associated with
silicosis is not instrumental in the development of the disease. Am. J. Physiol. Lung Cell Mol. Physiol.
292:L107–13
232. Helmby H, Grencis R. 2004. Interleukin 1 plays a major role in the development of Th2-mediated
immunity. Eur. J. Immunol. 34:3674–81
233. Schmitz J, Owyang A, Oldham E, Song Y, Murphy E, et al. 2005. IL-33, an interleukin-1-like cytokine
that signals via the IL-1 receptor-related protein ST2 and induces T helper type 2-associated cytokines.
Immunity 23:479–90
234. Nakanishi K, Yoshimoto T, Tsutsui H, Okamura H. 2001. Interleukin-18 is a unique cytokine that
stimulates both Th1 and Th2 responses depending on its cytokine milieu. Cytokine Growth Factor Rev.
12:53–72
235. Jin Y, Mailloux CM, Gowan K, Riccardi SL, LaBerge G, et al. 2007. NALP1 in vitiligo-associated
multiple autoimmune disease. N. Engl. J. Med. 356:1216–25
236. Fink SL, Cookson BT. 2005. Apoptosis, pyroptosis, and necrosis: mechanistic description of dead and
dying eukaryotic cells. Infect. Immun. 73:1907–16

264 Martinon · Mayor · Tschopp

 ANRV371-IY27-09 ARI 16 February 2009 8:57

237. Zychlinsky A, Prevost MC, Sansonetti PJ. 1992. Shigella flexneri induces apoptosis in infected
macrophages. Nature 358:167–69
238. Chen Y, Smith MR, Thirumalai K, Zychlinsky A. 1996. A bacterial invasin induces macrophage apoptosis
by binding directly to ICE. EMBO J. 15:3853–60
239. Hilbi H, Moss JE, Hersh D, Chen Y, Arondel J, et al. 1998. Shigella-induced apoptosis is dependent on
caspase-1 which binds to IpaB. J. Biol. Chem. 273:32895–900
240. Hersh D, Monack DM, Smith MR, Ghori N, Falkow S, Zychlinsky A. 1999. The Salmonella invasin
SipB induces macrophage apoptosis by binding to caspase-1. Proc. Natl. Acad. Sci. USA 96:2396–401
241. Mariathasan S, Weiss DS, Dixit VM, Monack DM. 2005. Innate immunity against Francisella tularensis
is dependent on the ASC/caspase-1 axis. J. Exp. Med. 202:1043–49
242. Cervantes J, Nagata T, Uchijima M, Shibata K, Koide Y. 2008. Intracytosolic Listeria monocytogenes
induces cell death through caspase-1 activation in murine macrophages. Cell Microbiol. 10:41–52
243. Reig N, Jiang A, Couture R, Sutterwala FS, Ogura Y, et al. 2008. Maturation modulates caspase-1-
independent responses of dendritic cells to Anthrax lethal toxin. Cell Microbiol. 10:1190–207
Annu. Rev. Immunol. 2009.27:229-265. Downloaded from arjournals.annualreviews.org

244. Yu JW, Fernandes-Alnemri T, Datta P, Wu J, Juliana C, et al. 2007. Pyrin activates the ASC pyroptosome
by Universidad Nacional Autonoma de Mexico on 03/24/09. For personal use only.

in response to engagement by autoinflammatory PSTPIP1 mutants. Mol. Cell 28:214–27

245. Scott AM, Saleh M. 2007. The inflammatory caspases: guardians against infections and sepsis. Cell Death
Differ. 14:23–31
246. Simi A, Tsakiri N, Wang P, Rothwell NJ. 2007. Interleukin-1 and inflammatory neurodegeneration.
Biochem. Soc. Trans. 35:1122–26
247. McConnell B, Vertino P. 2004. TMS1/ASC: the cancer connection. Apoptosis 9:5–18
248. Trendelenburg G. 2008. Acute neurodegeneration and the inflammasome: central processor for danger
signals and the inflammatory response? J. Cereb. Blood Flow Metab. 28:867–81
249. Roy N, Mahadevan MS, McLean M, Shutler G, Yaraghi Z, et al. 1995. The gene for neuronal apoptosis
inhibitory protein is partially deleted in individuals with spinal muscular atrophy. Cell 80:167–78
250. Halle A, Hornung V, Petzold GC, Stewart CR, Monks BG, et al. 2008. The NALP3 inflammasome is
involved in the innate immune response to amyloid-β. Nat. Immunol. 9:857–65
251. Gérard N, Caillaud M, Martoriati A, Goudet G, Lalmanach AC. 2004. The interleukin-1 system and
female reproduction. J. Endocrinol. 180:203–12
252. Caillaud M, Duchamp G, Gérard N. 2005. In vivo effect of interleukin-1β and interleukin-1RA on
oocyte cytoplasmic maturation, ovulation, and early embryonic development in the mare. Reprod. Biol.
Endocrinol. 3:26
253. Takehara Y, Dharmarajan AM, Kaufman G, Wallach EE. 1994. Effect of interleukin-1 β on ovulation
in the in vitro perfused rabbit ovary. Endocrinology 134:1788–93
254. Tong ZB, Gold L, Pfeifer KE, Dorward H, Lee E, et al. 2000. Mater, a maternal effect gene required
for early embryonic development in mice. Nat. Genet. 26:267–68
255. Qian J, Deveault C, Bagga R, Xie X, Slim R. 2007. Women heterozygous for NALP7/NLRP7 mutations
are at risk for reproductive wastage: report of two novel mutations. Hum. Mutat. 28:741
256. Slim R, Mehio A. 2007. The genetics of hydatidiform moles: new lights on an ancient disease. Clin.
Genet. 71:25–34
257. Murdoch S, Djuric U, Mazhar B, Seoud M, Khan R, et al. 2006. Mutations in NALP7 cause recurrent
hydatidiform moles and reproductive wastage in humans. Nat. Genet. 38:300–2
258. Shao W, Yeretssian G, Doiron K, Hussain SN, Saleh M. 2007. The caspase-1 digestome identifies the
glycolysis pathway as a target during infection and septic shock. J. Biol. Chem. 282:36321–29
259. Li J, Yin HL, Yuan J. 2008. Flightless-I regulates proinflammatory caspases by selectively modulating
intracellular localization and caspase activity. J. Cell Biol. 181:321–33
260. Young JL, Sukhova GK, Foster D, Kisiel W, Libby P, Schönbeck U. 2000. The serpin proteinase inhibitor
9 is an endogenous inhibitor of interleukin 1β-converting enzyme (caspase-1) activity in human vascular
smooth muscle cells. J. Exp. Med. 191:1535–44
261. Ray CA, Black RA, Kronheim SR, Greenstreet TA, Sleath PR, et al. 1992. Viral inhibition of inflamma-
tion: cowpox virus encodes an inhibitor of the interleukin-1 β converting enzyme. Cell 69:597–604

www.annualreviews.org • The Inflammasomes 265

 AR371-FM ARI 16 February 2009 15:37

Annual Review of
Immunology

Contents Volume 27, 2009

Frontispiece
Annu. Rev. Immunol. 2009.27:229-265. Downloaded from arjournals.annualreviews.org
by Universidad Nacional Autonoma de Mexico on 03/24/09. For personal use only.

Marc Feldmann p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p x
Translating Molecular Insights in Autoimmunity into Effective
Therapy
Marc Feldmann p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p1
Structural Biology of Shared Cytokine Receptors
Xinquan Wang, Patrick Lupardus, Sherry L. LaPorte,
and K. Christopher Garcia p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 29
Immunity to Respiratory Viruses
Jacob E. Kohlmeier and David L. Woodland p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 61
Immune Therapy for Cancer
Michael Dougan and Glenn Dranoff p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 83
Microglial Physiology: Unique Stimuli, Specialized Responses
Richard M. Ransohoff and V. Hugh Perry p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p119
The Liver as a Lymphoid Organ
Ian Nicholas Crispe p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p147
Immune and Inflammatory Mechanisms of Atherosclerosis
Elena Galkina and Klaus Ley p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p165
Primary B Cell Immunodeficiencies: Comparisons and Contrasts
Mary Ellen Conley, A. Kerry Dobbs, Dana M. Farmer, Sebnem Kilic,
Kenneth Paris, Sofia Grigoriadou, Elaine Coustan-Smith, Vanessa Howard,
and Dario Campana p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p199
The Inflammasomes: Guardians of the Body
Fabio Martinon, Annick Mayor, and Jürg Tschopp p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p229
Human Marginal Zone B Cells
Jean-Claude Weill, Sandra Weller, and Claude-Agnès Reynaud p p p p p p p p p p p p p p p p p p p p p p267

v
 AR371-FM ARI 16 February 2009 15:37

Aire
Diane Mathis and Christophe Benoist p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p287
Regulatory Lymphocytes and Intestinal Inflammation
Ana Izcue, Janine L. Coombes, and Fiona Powrie p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p313
The Ins and Outs of Leukocyte Integrin Signaling
Clare L. Abram and Clifford A. Lowell p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p339
Recent Advances in the Genetics of Autoimmune Disease
Peter K. Gregersen and Lina M. Olsson p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p363
Annu. Rev. Immunol. 2009.27:229-265. Downloaded from arjournals.annualreviews.org

Cell-Mediated Immune Responses in Tuberculosis

by Universidad Nacional Autonoma de Mexico on 03/24/09. For personal use only.

Andrea M. Cooper p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p393

Enhancing Immunity Through Autophagy
Christian Münz p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p423
Alternative Activation of Macrophages: An Immunologic Functional
Perspective
Fernando O. Martinez, Laura Helming, and Siamon Gordon p p p p p p p p p p p p p p p p p p p p p p p p451
IL-17 and Th17 Cells
Thomas Korn, Estelle Bettelli, Mohamed Oukka, and Vijay K. Kuchroo p p p p p p p p p p p p p p485
Immunological and Inflammatory Functions of the Interleukin-1
Family
Charles A. Dinarello p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p519
Regulatory T Cells in the Control of Host-Microorganism Interactions
Yasmine Belkaid and Kristin Tarbell p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p551
T Cell Activation
Jennifer E. Smith-Garvin, Gary A. Koretzky, and Martha S. Jordan p p p p p p p p p p p p p p p591
Horror Autoinflammaticus: The Molecular Pathophysiology of
Autoinflammatory Disease
Seth L. Masters, Anna Simon, Ivona Aksentijevich, and Daniel L. Kastner p p p p p p p p p621
Blood Monocytes: Development, Heterogeneity, and Relationship
with Dendritic Cells
Cedric Auffray, Michael H. Sieweke, and Frederic Geissmann p p p p p p p p p p p p p p p p p p p p p p p p669
Regulation and Function of NF-κB Transcription Factors in the
Immune System
Sivakumar Vallabhapurapu and Michael Karin p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p693

vi Contents